Skip to main content
Download PDF
Download ePub

Ca2+ signaling in vascular smooth muscle and endothelial cells in blood vessel remodeling: a review

Inflammation and Regeneration volume 44, Article number: 50 (2024) Cite this article

Abstract

Vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) act together to regulate blood pressure and systemic blood flow by appropriately adjusting blood vessel diameter in response to biochemical or biomechanical stimuli. Ion channels that are expressed in these cells regulate membrane potential and cytosolic Ca2+ concentration ([Ca2+]cyt) in response to such stimuli. The subsets of these ion channels involved in Ca2+ signaling often form molecular complexes with intracellular molecules via scaffolding proteins. This allows Ca2+ signaling to be tightly controlled in localized areas within the cell, resulting in a balanced vascular tone. When hypertensive stimuli are applied to blood vessels for extended periods, gene expression in these vascular cells can change dramatically. For example, alteration in ion channel expression often induces electrical remodeling that produces a depolarization of the membrane potential and elevated [Ca2+]cyt. Coupled with endothelial dysfunction blood vessels undergo functional remodeling characterized by enhanced vasoconstriction. In addition, pathological challenges to vascular cells can induce inflammatory gene products that may promote leukocyte infiltration, in part through Ca2+-dependent pathways. Macrophages accumulating in the vascular adventitia promote fibrosis through extracellular matrix turnover, and cause structural remodeling of blood vessels. This functional and structural remodeling often leads to chronic hypertension affecting not only blood vessels, but also multiple organs including the brain, kidneys, and heart, thus increasing the risk of severe cardiovascular events. In this review, we outline recent advances in multidisciplinary research concerning Ca2+ signaling in VSMCs and ECs, with an emphasis on the mechanisms underlying functional and structural vascular remodeling.

Background

Arteries consist of a three-layer structure: the intima, media, and adventitia, with endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and fibroblasts being the main component cells of each layer. The adventitia also includes resident immune cells and autonomic nerve endings. Arteries can be classified into three types on the basis of their vessel diameter and contractility patterns: elastic arteries, muscular arteries, and resistance arteries [1]. Elastic arteries are rich in elastic fibers and contribute to vascular compliance in response to cyclic high-pressure blood flow from the beating heart. In contrast, resistance arteries/arterioles can develop high contractile forces. Resistance arteries/arterioles dynamically change their diameter as a primary mechanism to regulate systemic blood pressure [2]. In healthy blood vessels, ECs produce nitric oxide (NO) which relaxes the vessel, whereas VSMCs contract in response to neurohumoral factors such as noradrenaline (NAd) and angiotensin (Ang) II [3]. Intracellular changes in Ca2+ concentration and Ca2+ signaling play a key role in regulating vascular diameter via ECs and VSMCs [4, 5].

It is now known that the steady state of blood vessels is regulated by shear stress due to blood flow and/or circumferential wall stress. When arteries are subjected to biochemical (e.g. neurohumoral factors) or biomechanical stimuli (e.g. high blood flow and pressure overload), these stress factors change, leading to deviation from the steady state [1]. Both VSMCs and ECs act as effectors to alter the diameter of the blood vessels and thus counteract these changes (Fig. 1A). If these stimuli are brief, the changes in vessel diameter are reversible. However, if pro-hypertensive stimuli continue for a prolonged time, blood vessels undergo functional and structural changes that are termed “vascular remodeling” (Fig. 1B) [6]. Initially, vascular remodeling functions as a compensatory mechanism, but over time, it leads to the disruption of homeostasis and the development of pathological conditions. Hypertension and atherosclerosis are examples of disorders caused by vascular remodeling. These progressive conditions are major causes of cardiovascular diseases, including ischemic heart disease and stroke, which rank as the first and second leading causes of death worldwide in 2020, according to a WHO report. Therefore, understanding the mechanisms underlying these pathologies is important for developing therapeutic agents that prevent cardiovascular events. In this review, we outline the mechanisms responsible for the functional remodeling that underlies increased contractility of blood vessels, and then describe structural remodeling associated with hypertension with a focus on the relationships between vascular component cells and leukocytes.

Fig. 1
figure 1

Progression and Classification of Vascular Remodeling. A When a stimulus is applied to an artery, stress factors (shear stress and circumferential wall stress) deviate from their normal steady state. The artery compensates for this perturbation by changing the vessel diameter through relaxation or contraction. If the stimulus is short-term, the change in vessel diameter is also temporary. B Conversely, if pro-hypertensive stimuli persists for a prolonged period, vascular component cells exhibit dramatic changes in transcription profiles, including ion channels that regulate intracellular Ca2+ signaling. This can result in electrical remodeling causing enhanced vasocontractility. At the same time, vasodilator capacity and endothelial barrier integrity are impaired. These changes cause functional remodeling. In addition, macrophages traffic to, and accumulate in the adventitia of blood vessels where they promote structural remodeling that enhances arterial stiffness and changes vessel diameter. In combination, these functional and structural remodeling lead to chronic hypertension. C Structural remodeling is classified on the basis of changes in vessel diameter and cross-sectional area. In hypertension, outward hypertrophic remodeling is observed in elastic arteries, whereas inward eutrophic remodeling or inward hypertrophic remodeling is observed in resistance arteries. In atherosclerosis, outward hypertrophic remodeling is observed in large vessels. EDHF: endothelium-derived hyperpolarizing factor, EGF: epidermal growth factor, ET-1: endothelin-1, NAd: noradrenaline

Full size image

Process of vascular remodeling in hypertension

In this review, we will describe vascular remodeling separately as “functional remodeling” and “structural remodeling”, respectively. Persistent hypertension-inducing stimuli largely alter the expression levels and activity of ion channels in VSMCs and ECs [7]. This pattern of change is called “electrical remodeling”. It is one of the main molecular components of functional remodeling that can result in increased vasocontractility [8, 9]. At the same time, there is endothelial dysfunction which is characterized by reduced endothelium-derived relaxation, inflammatory responses, and increased endothelial permeability. In addition, during process of structural remodeling, subsets of vascular component cells can produce chemokines and adhesion molecules, which then recruit specific types of immune cells, mainly macrophages, to the vessel wall. This may promote structural changes in blood vessels [1] (Fig. 1B). It is now known that in the vessel wall, macrophages produce matrix-degrading enzymes that promote the breakdown of the extracellular matrix (ECM) [10]. Moreover, both VSMCs and fibroblasts continuously produce fibrous collagen, resulting in increased vascular fibrosis and stiffness due to fragmentation of elastin and deposition of collagen and fibronectin [11]. This promotes chronic changes in vessel diameter due to structural remodeling [1] (Fig. 1B).

Structural remodeling is classified on the basis of changes in vessel diameter and cross-sectional area [12] (Fig. 1C). An increase in vessel diameter is denoted outward remodeling, whereas a decrease in diameter is called inward remodeling. If the vascular wall area increases or decreases, this is referred to as hypertrophic or hypotrophic remodeling, respectively; whereas no significant change in wall area is referred to as eutrophic remodeling. The phenotype of this remodeling is determined by the direction of pressure applied to the vessel and the contractility of VSMCs. In hypertension, when the pressure on elastic arteries (such as the aorta) persistently increases, there is an increase in circumferential wall stress, and consequently the aorta undergoes outward remodeling with ECM reconstruction in a dilated state (Fig. 1C). In this process, the proliferation of VSMCs and fibroblasts and ECM production from these cells increase the total wall thickness and stiffness, thereby reducing the circumferential wall stress [13] (Fig. 1C). Moreover, the stiffening of elastic arteries can increase the pulse wave velocity with each heart beat; this may result in damage to resistance vessels and microvessels in peripheral organs [14]. On the other hand, when the pressure on resistance vessels persistently increases during hypertension, the lumen radius decreases due to myogenic contraction to reduce circumferential wall stress. When the ECM stiffens under these conditions, resistance vessels undergo inward remodeling [1]. In resistance arteries that have been affected by essential hypertension, inward eutrophic remodeling characterized by VSMC rearrangement and ECM accumulation is observed. In contrast, in secondary hypertension, diabetes, and salt-sensitive hypertension, inward hypertrophic remodeling is promoted by severe endothelial damage, leading to VSMC proliferation [14] (Fig. 1C). Inward remodeling is thought to be a compensatory mechanism aimed at reducing wall stress and maintaining capillary bed pressures and flow within normal ranges. However, in the long term, it reduces the blood supply to peripheral organs, leading to end-organ damage [14]. There is a positive correlation between the remodeling of elastic arteries and resistance vessels, which are both critically involved in the progression of hypertensive pathology [15]. In summary, these functional and structural remodeling events initially manifest as adaptive responses to hypertensive stimuli. In contrast, over a prolonged periods of time these changes become maladaptive due to increased vascular tone and chronic arterial stiffening and narrowing, often leading to cardiovascular diseases such as essential and secondary hypertension, atherosclerosis, and aortic dissection (Fig. 1B).

Regulation of vascular tone by Ca2+ signaling in VSMCs and ECs

Vascular diameter is controlled by the contraction and relaxation of VSMCs. ECs cover the lumen of blood vessels and contact VSMCs through holes in the internal elastic lamina (IEL) (Fig. 2A). This structure is called the myoendothelial junction where ions and small molecules can pass between VSMCs and ECs through gap junctions [16]. In this section, we will describe the ion channels that play important roles in Ca2+ signaling-mediated regulation of vascular tone.

Fig. 2
figure 2

Ca2+ Signaling in Healthy Vascular Smooth Muscle Cells (VSMCs) and Endothelial Cells (ECs). A Diagrammatic illustration of the structure of blood vessels. ECs form myoendothelial junctions with VSMCs through holes/slits in the internal elastic lamina (IEL). The blue squares marked B-E in this figure define areas which are emphasized in the following panel (B to E). B Ca2+ channels involved in VSMC contraction. Cav1.2 channel functions as the main Ca2+-permeable channel. Stretch-sensitive ion channels, TRPM4/TRPC6, can activate Cav1.2 channels. TRPV4 channels are activated downstream of α1AR. Gq protein-coupled receptors produce IP3, which activates IP3R, and causes an increase in [Ca2+]cyt. C Ca2+ sparks activate nearby BKCa channels to induce STOCs and hyperpolarize the membrane potential. Caveolin1 and junctophilin2 are expressed in close proximity to RyR2 and BKCa channels. TRPV4 channels increase STOCs either by supplying Ca2+ directly to BKCa channels, or indirectly via Ca2+ sparks. Kv channels can hyperpolarize the membrane potential and suppress the activity of Cav1.2 channels. D ACh activates IP3R or TRPV4 channels and increases [Ca2+]cyt, resulting in NO and EDHF production. Physiological shear stress also activates TRPV4 channels to promote NO production. Stretch or shear sensitive Piezo1 channels activate TRPV4 channels via pannexin1/P2Y2 to promote NO production. Caveolae are important for NO and EDHF production by TRPV4 channels. E At the myoendothelial junction, Ca2+ influx through TRPV4 channels activates IKCa channels and eNOS to produce EDHF and NO, respectively. Kir2.1 channels amplify the hyperpolarization response by IKCa/SKCa channels. Gap junctions formed by connexin 37/40/43 transmit hyperpolarization to VSMCs. VSMCs are also hyperpolarized due to active K+ efflux mediated by Na+/K+-ATPase and Kir2.1 channels. AT1R: AngII receptor type 1, DAG: diacylglycerol, EDHF: endothelium-derived hyperpolarizing factor, ER: endoplasmic reticulum, PM: plasma membrane, SR: sarcoplasmic reticulum, STOC: spontaneous transient outward current, α1AR: α1 adrenergic receptor

Full size image

Ca2+ signaling in VSMCs in healthy arteries

VSMC contraction is promoted by stimuli such as sympathetic nerve activation, vasoconstrictors such as AngII and endothelin (ET)-1, and pressure overload. All of these stimuli increase cytosolic Ca2+ concentration ([Ca2+]cyt), which causes VSMC contraction through Ca2+/Calmodulin (CaM)-mediated activation of myosin light chain kinase and phosphorylation of myosin light chain [2]. When VSMCs are depolarized, [Ca2+]cyt increases mainly due to Ca2⁺ influx via L-type voltage-dependent Ca2⁺ (Cav1.2) channels [17] (Fig. 2B). Mechanical stretch also activates mechanosensitive cation channels such as, TRPC6 [18] and TRPM4 [19] depolarizing the membrane potential and opening Cav1.2 channels. Inositol 1,4,5-trisphosphate receptors (IP3R) in the sarcoplasmic reticulum (SR) release Ca2⁺ into the cytosol and cause vasoconstriction [20] (Fig. 2B). In contrast, ryanodine receptors (RyR) cause local Ca2+ release called Ca2⁺ sparks [21] that activate nearby large-conductance Ca2⁺-activated K⁺ (BKCa) channels to induce spontaneous transient outward currents (STOCs) [22] (Fig. 2C). This hyperpolarizes the membrane potential, closing L-type Ca2⁺ channels and inhibiting Ca2⁺ influx, resulting in vasodilation. We previously found that BKCa channels are localized to caveolae by binding to caveolin1, a caveolar forming protein, in VSMCs, and this promoted the frequency of STOCs [23]. In addition, junctophilin2 brings BKCa channels in caveolae and RyR on the SR into close proximity, which increases the efficiency of Ca2+ spark-STOC coupling and reduces the tension of mesenteric arteries [24]. In addition to BKCa channels, the voltage-dependent K+ (Kv) channel family (Kv1 [25], Kv2 [26], and Kv7 [27]) counteracts vasocontraction by suppressing Ca2+ influx from Cav1.2 channels by hyperpolarizing the membrane potentials (Fig. 2C).

TRPV4 is a cation channel that is activated by stretch, arachidonic acid, and temperature, and has attracted attention in vascular biology research recently. In VSMCs, TRPV4 channels form a molecular complex with RyR and BKCa channels [28]. This increases the Ca2+ spark activity by activating RyR, and increases STOCs by directly supplying Ca2+ to BKCa channels, thus decreasing vascular tone [28, 29] (Fig. 2C). TRPV4 channels also form a molecular complex with α1 adrenergic receptors (α1AR) and protein kinase C (PKC) via A-kinase anchoring protein (AKAP) 150. PKC activates TRPV4 channels, enhancing VSMC contraction induced by sympathetic nerve stimulation [29] (Fig. 2B). Super-resolution microscopy has revealed that the above two molecular complexes are localized in separate compartments on the plasma membrane of VSMCs [29]. Comparative analysis of EC-specific and SMC-specific TRPV4-knockout mice showed that TRPV4 channels in VSMCs cause vasoconstriction induced by phenylephrine and U46619, suggesting that TRPV4 channels primarily contribute to contraction in VSMCs [30].

Ca2+ signaling in ECs in healthy arteries

ECs produce NO via endothelial nitric oxide synthase (eNOS), which relaxes VSMC and dilates blood vessels. eNOS binds to caveolin1 in the steady state in an inactivated state [31]. When acetylcholine (ACh) released from parasympathetic nerve terminals binds to muscarinic ACh M3 receptors to increase [Ca2+]cyt, Ca2+/CaM binds to eNOS and dissociates from caveolin1, activating eNOS. On the other hand, in resistance vessels, vasodilation by endothelium-derived hyperpolarizing factor (EDHF) is dominant [32], contributing to local blood flow regulation. Although the actual nature of EDHF remains controversial, stimuli such as ACh and shear stress increase [Ca2+]cyt in ECs and subsequently activate intermediate-conductance Ca2+-activated K+ (IKCa) channels and small-conductance Ca2+-activated K+ (SKCa) channels. This results in membrane hyperpolarization, which is transmitted to VSMCs via gap junctions in myoendothelial junction to cause VSMC relaxation [33].

TRPV4 [34] and Piezo1 [35] are ion channels that allow Ca2+ influx into ECs in response to ACh and shear stress. TRPV4 channels are localized in caveolae and form molecular complexes with connexin 43 and SKCa3 channels to induce EDHF [36, 37] (Fig. 2D). In ECs from caveolin1 knockout mice, ACh-induced NO production is increased, while reduced TRPV4 channel activity and loss of ACh-induced EDHF are observed [36]. Laminar shear stress induces TRPV4/eNOS/caveolin1 microdomains at the downstream end of ECs, which activate eNOS through TRPV4 channel-mediated Ca2+ influx and suppress the expression of NF-kB-dependent inflammatory genes [38]. Piezo1 channels are localized on the luminal side of ECs or at the junction between ECs. They are activated by shear stress and are permeable to Ca2+. Piezo1 channels are required for fluid-directed alignment of ECs [35]. They activate eNOS by promoting ATP release via pannexin and activating the purinergic P2Y2 receptor, which phosphorylates eNOS at Ser1177 [39] (Fig. 2D).

In the myoendothelial junction, TRPV4 channels form a complex with PKC via AKAP150. ACh stimulation activates TRPV4 channels and evokes EDHF by activating IKCa channels [40] (Fig. 2E). The inwardly rectifying K+ (Kir2.1) channel amplifies this hyperpolarization [33]. An increase in the extracellular K+ concentration at myoendothelial junction shifts the K+ equilibrium potential towards more depolarized potentials, promoting K+ efflux via Kir2.1 channels, hyperpolarizing the membrane potential of ECs and VSMCs [41]. The Na+/K+ ATPase enhances EDHF by K+ uptake and Na+ release which hyperpolarizes the membrane potential [42].

Functional remodeling of arteries in hypertension

In hypertension, peripheral vascular resistance increases continuously due to both functional and structural remodeling of systemic arteries. In both hypertensive patients and animal models, functional remodeling (characterized by decreased endothelial function, increased vascular contractility, and increased responsiveness to agonists and mechanical stimuli) are commonly observed [7, 15]. Electrical remodeling due to changes in the expression and activity of Ca2+ channels or K+ channels underlies functional remodeling [8, 9] (Fig. 1B). Below, we discuss recent findings on electrical/functional remodeling.

Electrical remodeling in hypertensive VSMCs

It has been reported that continuous pressure overload for two days on arteries increases the expression of Cav1.2 channels and depolarizes the membrane potential (from −50 mV to −40 mV) [43] (Fig. 3A). In this study, the expression of Cav1.2 channels increased simply by culturing arteries in high KCl medium, suggesting that continuous membrane depolarization maintains the increased expression of Cav1.2. ET-1 induces reactive oxygen species (ROS) production from mitochondria via Ca2+ release from IP3R and promotes Cav1.2 transcription via the NF-kB pathway [44]. Mineralocorticoid receptors (MR) in VSMCs increase Cav1.2 channel and AngII receptor (AT1R) expression, AngII-induced ROS production, and vascular tone by downregulating miR155 in an age-dependent hypertension model [45]. During hypertension, not only the expression level of Cav1.2 channels but also its Ca2+ permeability increases. A “Ca2+ sparklet” is a very small, localized and transient influx of Ca2+ mainly through Cav1.2 channels. In VSMCs, Cav1.2 clusters form molecular complexes with AKAP150 and PKCα [46]. AngII promotes PKC-mediated phosphorylation of Cav1.2 channels at Ser1928, increases the number of Cav1.2 channels in the clusters, thereby promoting Ca2+ sparklets [47]. (Fig. 3A). This cascade results in increased [Ca2+]cyt and enhanced vasoconstriction. At the same time, the calcineurin-NFAT system is also activated, and the transcription and expression of Kv2.1 channels [48] and the BKCa channel β1 subunit [49] are reduced, depolarizing the membrane potential and maintaining the hypertensive state. This increase in Ca2+ sparklets is dependent on the scaffolding protein AKAP150, since knockout of AKAP150 blunted AngII-induced hypertension [46]. In spontaneously hypertensive rats (SHRs), upregulation of AKAP150 increases Ca2+ sparklet activity mediated by PKC. Interestingly, it has been reported that exercise reduces the expression of AKAP150 in SHRs, which normalizes Ca2+ sparklet activity and blood AngII concentration, and blood pressure [50].

Fig. 3
figure 3

Electrical remodeling in hypertensive VSMCs and ECs. A In hypertensive VSMCs, the expression and activity (cluster formation) of Cav1.2 channels are enhanced. In addition, increased expression of AT1R and IP3R and increased formation of the α1AR-TRPV4 complexes can increase VSMC contractility. B Decreased activity of BKCa channels and dissociation of TRPV4 channel reduce STOCs. Kv channel expression also decreases, resulting in depolarization of the membrane potential. C In ECs, dissociation of TRPV4 channel and eNOS reduces NO production. Activation of Piezo1 channels can cause sustained Ca2+ influx from TRPV4 channels due to sustained high shear stress, enhancing endothelial permeability. In addition, Piezo1 channels activate a NF-κB pathway mediated by panexin1/P2Y2 in response to turbulent laminar flow. D In myoendothelial junctions, downregulation or oxidation of AKAP150 reduce TRPV4 channel activity and reduce EDHF and NO production. Kir2.1 channel and gap junction component proteins are also downregulated in hypertensive ECs and VSMCs localized at the myoendothelial junction. AA: arachidonic acid, AT1R: AngII receptor type 1, EDHF: endothelium-derived hyperpolarizing factor, EET: epoxytrienoic acid, PLA2: phospholipase A2, PM: plasma membrane, SR: sarcoplasmic reticulum, STOC: spontaneous transient outward current, α1AR: α1 adrenergic receptor

Full size image

TRPV4 channels are involved in both the contraction response mediated by the AKAP150/α1AR/PKC molecular complex and the vascular relaxation response mediated by the RyR/BKCa channel molecular complex [29]. In VSMCs from hypertensive patients and AngII-induced hypertension models, the TRPV4/AKAP150/α1AR/PKC molecular complex was increased, enhancing the contribution of TRPV4 channels to vasoconstriction (Fig. 3A), whereas the TRPV4/RyR/BKCa channel molecular complex was decreased (Fig. 3B) [29]. Similar results were observed in obesity-induced hypertension, suggesting that TRPV4 channel activity contributes to increased tone, elevated blood pressure, and medial thickening during hypertension [30]. Piezo1 channels are highly expressed in VSMCs of resistance vessels and depolarize the membrane potential in response to mechanical stimulation, whereas they are not involved in myogenic tone [51]. In AngII- or DOCA/salt-induced hypertension models, Piezo1 contributes to medial thickening by increasing transglutaminase expression (Fig. 3A). In addition, increased expression of AT1R [45] and IP3R [52] also contribute to an increase in VSMC contractility. Since AT1R can be activated by pressure overload alone in an AngII independent manner [53], both increased expression and high intraluminal pressure may synergistically promote vasocontractility in VSMCs.

Ca2+ spark-STOC coupling is important for maintaining tone, but it is known that this coupling is impaired in hypertensive conditions (Fig. 3B). It has been proposed that genetic deletion [54] or reduced expression [55] of the BKCa channel β1 subunit reduces Ca2+ sensitivity, making it impossible to induce STOCs in response to Ca2+ sparks. In BPH/2 mice, dissociation of the plasma membrane and SR occurs in cerebral resistance arteries, and Ca2+ spark-STOC coupling is weakened, leading to reduced cerebral blood flow and vascular dementia [56]. In addition, the expression of Kv channels such as Kv1 [25], Kv2.1 [26], and Kv7 [27] is reduced, which is thought to depolarize the membrane potential. The synergistic effect of increased expression/activity of Cav1.2 channels and depolarization increase [Ca2+]cyt, enhancing vasocontraction.

Electrical remodeling in hypertensive ECs

Healthy ECs suppress excessive contraction of arteries by NO or EDHF, but in hypertensive conditions, pressure overload, turbulent flow, and humoral factors such as AngII and ET-1 cause superoxide production via NADPH oxidase. Superoxide reduces the bioavailability of NO by uncoupling eNOS and converting NO to ONOO−, thereby attenuating vasorelaxation and increasing peripheral vascular resistance [57]. In AngII-induced hypertension mice, the molecular coupling between TRPV4 channels and eNOS in aortic ECs is reduced, resulting in decreased NO production [58] (Fig. 3C). The turbulent flow leads to abnormal activation of Piezo1 channels, which activates the pannexin1-P2Y2-PLC-α5 integrin-FAK pathway [59]. FAK induces endothelial activation and transcription of pro-inflammatory factors via the NF-kB pathway (Fig. 3C). Piezo1 channels also activate TRPV4 channels via phospholipase A2, causing a sustained increase in [Ca2+]cyt [60]. This leads to the disassembly of adherent junctions between ECs and increased endothelial permeability. These findings suggest that the state of blood flow may alter the signal transduction initiated by Piezo1 and TRPV4 channels by changing the components of molecular complexes containing these channels. Thus, during abnormal blood flow, Piezo1 and TRPV4 channels promote leukocyte adhesion to ECs and infiltration into the subendothelial space, leading to inflammation in the vascular wall.

At the myoendothelial junction of AngII-induced hypertension mice, AKAP150 expression is attenuated, and ACh-induced EDHF generation by the TRPV4/AKAP150/PKC complex is reduced [40] (Fig. 3D). Importantly, the density of myoendothelial junctions is reduced and their local IP3-stimulated Ca2+ signals are blunted in mesenteric arterioles of SHRs [61]. In an obesity-induced hypertension model, NOX1 and iNOS expression are increased at the myoendothelial junction of ECs, converting NO to ONOO− [62]. ONOO− oxidizes Cys36 of AKAP150, dissociating PKC, and attenuating TRPV4 channel activity and thus EDHF.

In a hypertensive vascular dementia model based on BPH/2 mice, blood supply to metabolically active areas of the brain (functional hyperemia) was reduced through reduced activity of Kir2.1 channels in cerebral microvascular ECs [63]. Interestingly, amlodipine, but not losartan, inhibited this functional reduction in hyperemia. This difference is blunted by additional treatment with eplerenone, indicating pro-dementia roles of aldosterone. This suggests that Kir2.1 channels may be a target for preventing cognitive decline in late life in hypertensive patients treated with AT1R blockers.

Structural remodeling of arteries in hypertension

In hypertension, structural remodeling (mainly outward remodeling of elastic vessels and inward remodeling of resistance vessels) occurs due to long-term pro-hypertensive stimuli (Fig. 1B). VSMC proliferation is suppressed at steady state and in the early stage of hypertension, but as hypertension progresses, VSMCs enter the cell cycle and begin to proliferate [64]. In this process, Ca2+ signals are important (for review, see [65,66,67,68]). Previous studies have revealed that leukocytes such as macrophages accumulating in the vascular wall promote turnover of the ECM and cause VSMC migration and proliferation, which are very important for the initiation and progression of structural remodeling in various vascular diseases including hypertension. In this section, we will first outline the role of immune cells in hypertension. Next, we will summarize research findings that have clarified the molecular mechanism by which blood flow disorders and pressure overload cause leukocyte accumulation in the vascular wall based on data sets obtained from in vivo and ex vivo experimental systems.

Immune cells relating to structural remodeling

Experiments using C-C motif chemokine receptor (CCR) 2 knockout mice [69] and LysM-iDTR mice (in which monocytes are depleted) [70] have revealed that monocytes and macrophages play crucial roles in the development of hypertension. The macrophages that accumulate in the adventitia in response to AngII initially exhibit M1-like (classically activated) properties but shift to M2-like (alternatively activated) macrophages after 14 days, leading to chronic hypertension through collagen deposition and elastin degradation [71] (Fig. 4A). Mechanical stress on blood vessels and Ang II stimulation increase the expression of CCL2 in ECs [72], VSMCs [73], and adventitious fibroblasts [74], leading to monocyte accumulation in the vascular wall and differentiation into macrophages (Fig. 4A). In addition, during hypertension, the expression of C-X-C motif chemokine ligand (CXCL) 1 in the aorta and CXCR2 in monocytes/macrophages increases, leading to increased macrophage accumulation [75]. Accumulated macrophages produce ROS and cytokines, leading to further ROS production by VSMCs and ECs and resulting in elevated blood pressure, aortic fibrosis, inflammation, and endothelial dysfunction.

Fig. 4
figure 4

Structural Remodeling mediated by Interactions between Vascular Component and Immune Cells. A Pressure load changes on blood vessels and/or Ang II initiate or promote the production of chemokines from ECs, VSMCs, and adventitial fibroblasts, leading to monocyte and macrophage infiltration into the vessel wall. ROS produced by macrophages and vascular component cells cause vascular damage. B CD8+ T cells and probably Th1 cells accumulate in the vessel wall through CCL5-CCR5 interactions, where they produce IFNγ and TNFα. In addition, Th17 cells produce IL-17 and superoxide. These cytokines and ROS both can promote hypertension. C Elevated local blood flow in the mesenteric artery increases circumferential stress in the vascular wall by stretching VSMCs and depolarizing the membrane potential. The scaffolding protein caveolin1 mediates the formation of a molecular complex consisting of Cav1.2 channels, CaMKK2, and CaMK1. Ca2+ influx through Cav1.2 channels can activate CaMKK2 and CaMK1, and this causes CaMK1 to translocate to the nucleus where it induces the transcription of genes that encodes chemokines and adhesion molecules such as CXCL1, CCL2, P-selectin, and VCAM1. As a result, monocytes and macrophages accumulate in the adventitia, leading to outward remodeling. BP: blood pressure, CaMKK2: Ca2+/CaM dependent kinase kinase2, PM: plasma membrane

Full size image

For over 20 years, it has been known that T cells accumulate around blood vessels and in the kidneys in the setting of progressive hypertension and that immunosuppressants lower blood pressure [76, 77] (Fig. 4A). To date, it has been revealed that among T cell subsets, interferon (IFN) γ-producing CD8+ cells are involved in blood pressure elevation and vascular rarefaction in the kidneys [78]. Moreover, CCL5-CCR5 is involved in the infiltration of T cells into the vascular wall [79] (Fig. 4B). CD4+-derived Th17 cells produce superoxide via interleukin (IL)-17A, contributing to blood pressure elevation, endothelial dysfunction, fibrosis, and sodium reabsorption in AngII-induced hypertension [80]. In hypertension, efferent sympathetic nerve activity increases [3], and these immune cells are activated in secondary lymphoid tissues such as the spleen and lymph nodes and in the kidney, and then distributed throughout the body, enhancing inflammation [81].

Pressure-induced structural remodeling

Either pressure overload (150 mmHg) or AngII treatment can result in the production of transforming growth factor α and transactivation of epidermal growth factor receptor (EGFR) secondary to ROS production by NADPH oxidase in mouse carotid arteries [82]. This actives the NF-kB pathway, promoting survival of vascular cells, upregulating CCL2, CXCL1, IL-6, and vascular cell adhesion molecule (VCAM) 1, and increasing monocyte accumulation in the vascular wall, and thus resulting in outward remodeling [83]. Importantly, ONOO−-induced matrix metalloproteinase (MMP) 9 expression is required for this outward remodeling [84]. A similar function of MMP9 is also observed in outward remodeling that occurs in the model of early stages of atherosclerosis [85] and vascular injury following carotid artery ligation [86]. MMP9 expression is increased in elastic vessels in the early stages of hypertension, and it is thought that the compensatory outward remodeling contributes to the suppression of systolic blood pressure rise, the reduction of pulse pressure, and the homeostatic maintenance of vessel compliance.

In contrast to these ROS-mediated pathways, we have found that Ca2+ signaling induced by mechanical stress applied to blood vessels is converted into gene transcription via excitation-transcription (E-T) coupling [48, 67], leading to vascular remodeling (Fig. 4C). In the mesenteric artery ligation model, we showed that increased circumferential wall stress accompanying increases blood flow in the mesenteric artery activates Cav1.2 channels in VSMCs and an associated increase in Ca2+ influx into the cytoplasm. This then activates Ca2+/CaM dependent kinase kinase (CaMKK) 2 and CaMK1, which forms a complex with Cav1.2 channels via the caveolin1 [23], and CaMK1 translocates to the nucleus, where it activates the transcription factor CREB [87]. The aggregate result is an upregulation of the expression of genes encoding chemokines and adhesion molecules such as CXCL1, CCL2, P-selectin, and VCAM1, again resulting in macrophage accumulation in the adventitia and outward remodeling [88]. Macrophage accumulation and outward remodeling due to the increased circumferential wall stress are attenuated in caveolin1 knockout mice or by administration of the CaMKK2 inhibitor STO609. These findings suggest that VSMCs can produce inflammatory factors such as chemokines, which attract monocytes and macrophages to the vessel wall (mainly in the adventitia).

In atherosclerosis, monocytes, macrophages, and T cells primarily infiltrate from the luminal side of blood vessels. In contrast, it has been shown that in hypertension, monocytes, macrophages, and T cells accumulate on the adventitia side of blood vessels. Similar trends are also seen in aortic dissection [89] and pulmonary hypertension [90]. Although the ability of VSMCs to produce inflammatory cytokines is weaker than that of immune cells, the large number of VSMCs in blood vessels compared with other cell types suggests that the inflammatory response of VSMCs may be sufficient to trigger subsequent immune responses [91]. While VSMCs are not in direct contact with either the vessel lumen or extravascular regions, arteries are permeable to low-molecular-weight compounds and albumin (66 kDa) [92]. In particular, since the adventitia lacks physical barriers such as the tight junctions within the endothelium, chemokines (8–12 kDa [93]) produced by VSMCs are likely to diffuse relatively freely within the vessel, thereby promoting the infiltration of monocytes and macrophages into the adventitia.

It is now well established that caveolin1 is an aggravating factor for hypertension and atherosclerosis. In an AngII-induced hypertension model created in caveolin1 knockout mice, no difference was observed in systemic blood pressure, but phosphorylation of EGFR, upregulation of caveolin1 and adventitial VCAM1, medial thickening, and fibrosis were suppressed in the aorta, coronary artery, and renal artery [94]. Plaque formation was also suppressed in caveolin1 and eNOS double knockout mice, revealing that the protective effect of caveolin1 deficiency is not related to NO [95]. Caveolin1 deficiency suppressed LDL transport through ECs, fibronectin accumulation, inflammatory responses, and macrophage infiltration. Furthermore, the distribution of caveolae showed a different pattern in areas exhibiting plaque formation compared with those that did not. Both activation of the NLRP3 inflammasome and production of IL-1β in macrophages are important for the development of hypertension [96]. When we investigated the role of caveolin1 in macrophages, we unexpectedly found that lipopolysaccharide-induced transcription of pro-inflammatory factors, purinergic P2X7 receptor activity, and IL-1β production after ATP stimulation were all increased in caveolin1 knockout macrophages [97]. This pattern of results revealed that, unlike VSMCs and ECs, caveolin1 suppresses inflammatory responses in these macrophages.

Prospects for the development of new therapeutic drugs for vascular diseases

To date, although excellent drugs have been developed for hypertension, there are remaining clinical challenges and knowledge gaps called a “residual risk” in hypertension [98]. It has been shown that the risk for significant cardiovascular complications (e.g. coronary disease, stroke, and cardiovascular death) of well-treated and controlled hypertensive subjects is higher than that of untreated normotensive subjects at the same blood pressure level [99]. Recently, the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) trial demonstrated that the IL-1β antagonist canakinumab significantly suppressed the occurrence of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular death [100]. In addition, it has been reported that anti-inflammatory drugs such as colchicine and tumor necrosis factor inhibitors alleviate hypertension and suppress cardiovascular events in atherosclerosis [93]. In the future, it may be necessary to introduce drugs into conventional hypertension treatment that not only lower blood pressure but also suppress inflammation in blood vessels and other organs. In this regard, some of the molecules and signaling pathways discussed in this review may also become new therapeutic targets. Caveolin1 is involved in the formation of some vascular diseases, including hypertension [94], atherosclerosis [95], and pulmonary hypertension [101]. The membrane-permeable peptide “cavtratin” that mimics the functions of caveolin1 shows therapeutic effects on some cancers [102] and an intraocular angiogenesis [103] due to the inhibition of angiogenesis. In contrast, “cavnoxin” has also been developed as a competitive peptide of caveolin1. Its antihypertensive effects are due to increasing the activity of eNOS [104]. In addition, a specific inhibitor of Cav1.2 channels localized in caveolae has been developed [105]. Unfortunately, however, it turned out that the inhibitor did not have a preventive effect on heart failure [106]. Thus, it may now be possible to specifically control the function of target molecules that are localized in caveolae. This capability enables lowering [Ca2+]cyt, increasing NO production, and preventing inflammatory responses and structural remodeling. The scaffolding molecule AKAP150 (AKAP5 in human) (Fig. 3) is also associated with hypertension [40, 46, 62]. Indeed, it has been shown that exercise can reduce AKAP150 in VSMCs and lower blood pressure [50]. Therefore, AKAP5 may be a promising target for hypertension by specifically modulating hypertensive signaling pathways.

Conclusion

Ca2+ signaling in both VSMCs and ECs plays critical roles in maintaining vascular homeostasis. Sustained hypertensive stress on blood vessels induces both functional and structural remodeling, at least in part, by modifying Ca2+-dependent pathways. Thus, hypertension develops through the cooperation of functional remodeling (enhanced contractility) and structural remodeling (arterial stiffening). It is known that hypertension can be caused by abnormalities not only in blood vessels but also in other organs such as the central nervous system, sympathetic nervous system, immune system, and/or the kidneys. As a consequence, in addition to research focusing on the molecular complexes in vascular constituent cells, it will be necessary to reveal the significance of these molecular complexes at organ, inter-organ, and whole body levels to achieve optimal development and validation of new antihypertensive drugs that may prevent adverse cardiovascular events.

Data availability

Not applicable.

Abbreviations

Ang:

Angiotensin

AT1R:

AngII receptor type 1

EC:

Endothelial cell

eNOS:

Endothelial nitric oxide synthase

EDHF:

Endothelium-derived hyperpolarizing factor

ECM:

Extracellular matrix

IP3R:

Inositol 1,4,5-trisphosphate receptor

IKCa channel:

Intermediate-conductance Ca2+-activated K+ channel

IEL:

Internal elastic lamina

[Ca2+]cyt :

Cytosolic Ca2+ concentration

Kir  channel:

Inwardly rectifying K+ channel

BKCa  channel:

Large-conductance Ca2+-activated K+ channel

MMP:

Matrix metalloproteinase

NLRP:

NLR family pyrin containing

ROS:

Reactive oxygen species

RyR:

Ryanodine receptor

SR:

Sarcoplasmic reticulum

SKCa  channel:

Small-conductance Ca2+-activated K+ channel

STOC:

Spontaneous transient outward current

SHR:

Spontaneously hypertensive rat

VSMC:

Vascular smooth muscle cell

Kv  channel:

Voltage-dependent K+ channel

α1AR:

α1 Adrenergic receptor

References

  1. Humphrey JD. Mechanisms of vascular remodeling in hypertension. Am J Hypertens. 2021;34(5):432–41. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/ajh/hpaa195.

    Article  PubMed  Google Scholar 

  2. Lacolley P, Regnault V, Segers P, Laurent S. Vascular smooth muscle cells and arterial stiffening: relevance in development, aging, and disease. Physiol Rev. 2017;97(4):1555–617. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/physrev.00003.2017.

    Article  CAS  PubMed  Google Scholar 

  3. Harrison DG, Coffman TM, Wilcox CS. Pathophysiology of hypertension: the mosaic theory and beyond. Circ Res. 2021;128(7):847–63. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCRESAHA.121.318082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Billaud M, Lohman AW, Johnstone SR, Biwer LA, Mutchler S, Isakson BE. Regulation of cellular communication by signaling microdomains in the blood vessel wall. Pharmacol Rev. 2014;66(2):513–69. https://doiorg.publicaciones.saludcastillayleon.es/10.1124/pr.112.007351.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mironova GY, Kowalewska PM, El-Lakany M, Tran CHT, Sancho M, Zechariah A, et al. The conducted vasomotor response and the principles of electrical communication in resistance arteries. Physiol Rev. 2024;104(1):33–84. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/physrev.00035.2022.

    Article  CAS  PubMed  Google Scholar 

  6. Lee RM, Dickhout JG, Sandow SL. Vascular structural and functional changes: their association with causality in hypertension: models, remodeling and relevance. Hypertens Res. 2017;40(4):311–23. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/hr.2016.145.

    Article  PubMed  Google Scholar 

  7. Touyz RM, Alves-Lopes R, Rios FJ, Camargo LL, Anagnostopoulou A, Arner A, et al. Vascular smooth muscle contraction in hypertension. Cardiovasc Res. 2018;114(4):529–39. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/cvr/cvy023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Daghbouche-Rubio N, López-López JR, Pérez-García MT, Cidad P. Vascular smooth muscle ion channels in essential hypertension. Front Physiol. 2022;13:1016175. https://doiorg.publicaciones.saludcastillayleon.es/10.3389/fphys.2022.1016175.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Joseph BK, Thakali KM, Moore CL, Rhee SW. Ion channel remodeling in vascular smooth muscle during hypertension: implications for novel therapeutic approaches. Pharmacol Res. 2013;70(1):126–38. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.phrs.2013.01.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis. Circ Res. 2002;90(3):251–62. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/res.90.3.251.

    Article  CAS  PubMed  Google Scholar 

  11. Jaminon A, Reesink K, Kroon A, Schurgers L. The role of vascular smooth muscle cells in arterial remodeling: focus on calcification-related processes. Int J Mol Sci. 2019;20(22). https://doiorg.publicaciones.saludcastillayleon.es/10.3390/ijms20225694.

  12. Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, et al. Vascular remodeling. Hypertension. 1996;28(3):505–6.

    CAS  PubMed  Google Scholar 

  13. Wu J, Thabet SR, Kirabo A, Trott DW, Saleh MA, Xiao L, et al. Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res. 2014;114(4):616–25. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCRESAHA.114.302157.

    Article  CAS  PubMed  Google Scholar 

  14. Brandt MM, Cheng C, Merkus D, Duncker DJ, Sorop O. Mechanobiology of microvascular function and structure in health and disease: focus on the coronary circulation. Front Physiol. 2021;12:771960. https://doiorg.publicaciones.saludcastillayleon.es/10.3389/fphys.2021.771960.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Brown IAM, Diederich L, Good ME, Delalio LJ, Murphy SA, Cortese-Krott MM, et al. Vascular smooth muscle remodeling in conductive and resistance arteries in hypertension. Arterioscler Thromb Vasc Biol. 2018;38(9):1969–85. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/atvbaha.118.311229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sandow SL, Hill CE. Incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat is suggestive of a role in endothelium-derived hyperpolarizing factor-mediated responses. Circ Res. 2000;86(3):341–6. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.res.86.3.341.

    Article  CAS  PubMed  Google Scholar 

  17. Moosmang S, Schulla V, Welling A, Feil R, Feil S, Wegener JW, et al. Dominant role of smooth muscle L-type calcium channel Cav1.2 for blood pressure regulation. EMBO J. 2003;22(22):6027–34. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/emboj/cdg583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Welsh DG, Morielli AD, Nelson MT, Brayden JE. Transient receptor potential channels regulate myogenic tone of resistance arteries. Circ Res. 2002;90(3):248–50.

    Article  CAS  PubMed  Google Scholar 

  19. Earley S, Waldron BJ, Brayden JE. Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ Res. 2004;95(9):922–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.res.0000147311.54833.03.

    Article  CAS  PubMed  Google Scholar 

  20. Lin Q, Zhao G, Fang X, Peng X, Tang H, Wang H, et al. IP3 receptors regulate vascular smooth muscle contractility and hypertension. JCI Insight. 2016;1(17). https://doiorg.publicaciones.saludcastillayleon.es/10.1172/jci.insight.89402.

  21. Kaßmann M, Szijártó IA, García-Prieto CF, Fan G, Schleifenbaum J, Anistan YM, et al. Role of ryanodine type 2 receptors in elementary Ca2+ signaling in arteries and vascular adaptive responses. J Am Heart Assoc. 2019;8(9):e010090. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/jaha.118.010090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nelson MT, Cheng H, Rubart M, Santana LF, Bonev AD, Knot HJ, et al. Relaxation of arterial smooth muscle by calcium sparks. Science. 1995;270(5236):633–7.

    Article  CAS  PubMed  Google Scholar 

  23. Suzuki Y, Yamamura H, Ohya S, Imaizumi Y. Caveolin-1 facilitates the direct coupling between large conductance Ca2+-activated K+ (BKCa) and Cav1.2 Ca2+ channels and their clustering to regulate membrane excitability in vascular myocytes. J Biol Chem. 2013;288(51):36750–61. https://doiorg.publicaciones.saludcastillayleon.es/10.1074/jbc.M113.511485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Saeki T, Suzuki Y, Yamamura H, Takeshima H, Imaizumi Y. A junctophilin-caveolin interaction enables efficient coupling between ryanodine receptors and BKCa channels in the Ca2+ microdomain of vascular smooth muscle. J Biol Chem. 2019. https://doiorg.publicaciones.saludcastillayleon.es/10.1074/jbc.RA119.008342.

  25. Plane F, Johnson R, Kerr P, Wiehler W, Thorneloe K, Ishii K, et al. Heteromultimeric Kv1 channels contribute to myogenic control of arterial diameter. Circ Res. 2005;96(2):216–24. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.Res.0000154070.06421.25.

    Article  CAS  PubMed  Google Scholar 

  26. Amberg GC, Santana LF. Kv2 channels oppose myogenic constriction of rat cerebral arteries. Am J Physiol Cell Physiol. 2006;291(2):C348–56. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/ajpcell.00086.2006.

    Article  CAS  PubMed  Google Scholar 

  27. Jepps TA, Chadha PS, Davis AJ, Harhun MI, Cockerill GW, Olesen SP, et al. Downregulation of Kv7.4 channel activity in primary and secondary hypertension. Circulation. 2011;124(5):602–11. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circulationaha.111.032136.

  28. Earley S, Heppner TJ, Nelson MT, Brayden JE. TRPV4 forms a novel Ca2+ signaling complex with ryanodine receptors and BKCa channels. Circ Res. 2005;97(12):1270–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.RES.0000194321.60300.d6.

    Article  CAS  PubMed  Google Scholar 

  29. Chen YL, Daneva Z, Kuppusamy M, Ottolini M, Baker TM, Klimentova E, et al. Novel smooth muscle Ca2+-signaling nanodomains in blood pressure regulation. Circulation. 2022;146(7):548–64. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circulationaha.121.058607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhu Y, Chu Y, Wang S, Tang J, Li H, Feng L, et al. Vascular smooth muscle TRPV4 (Transient Receptor Potential Vanilloid Family Member 4) channels regulate vasoconstriction and blood pressure in obesity. Hypertension. 2023;80(4):757–70. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/hypertensionaha.122.20109.

    Article  CAS  PubMed  Google Scholar 

  31. Michel JB, Feron O, Sacks D, Michel T. Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. J Biol Chem. 1997;272(25):15583–6. https://doiorg.publicaciones.saludcastillayleon.es/10.1074/jbc.272.25.15583.

    Article  CAS  PubMed  Google Scholar 

  32. Brandes RP, Schmitz-Winnenthal F-H, Félétou M, Gödecke A, Huang PL, Vanhoutte PM, et al. An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice. Proc Natl Acad Sci U S A. 2000;97(17):9747–52. https://doiorg.publicaciones.saludcastillayleon.es/10.1073/pnas.97.17.9747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sonkusare SK, Dalsgaard T, Bonev AD, Nelson MT. Inward rectifier potassium (Kir2.1) channels as end-stage boosters of endothelium-dependent vasodilators. J Physiol. 2016;594(12):3271–85. https://doiorg.publicaciones.saludcastillayleon.es/10.1113/JP271652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. KöHler R, Heyken W-T, Heinau P, Schubert R, Si H, Kacik M, et al. Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation. Arterioscler Thromb Vasc Biol. 2006;26(7):1495–502. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.atv.0000225698.36212.6a.

    Article  PubMed  Google Scholar 

  35. Li J, Hou B, Tumova S, Muraki K, Bruns A, Ludlow MJ, et al. Piezo1 integration of vascular architecture with physiological force. Nature. 2014;515(7526):279–82. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/nature13701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Saliez J, Bouzin C, Rath G, Ghisdal P, Desjardins F, Rezzani R, et al. Role of caveolar compartmentation in endothelium-derived hyperpolarizing factor-mediated relaxation: Ca2+ signals and gap junction function are regulated by caveolin in endothelial cells. Circulation. 2008;117(8):1065–74. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.107.731679.

  37. Lu T, Wang XL, Chai Q, Sun X, Sieck GC, Katusic ZS, et al. Role of the endothelial caveolae microdomain in shear stress-mediated coronary vasorelaxation. J Biol Chem. 2017;292(46):19013–23. https://doiorg.publicaciones.saludcastillayleon.es/10.1074/jbc.M117.786152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hong S-G, Ashby JW, Kennelly JP, Wu M, Steel M, Chattopadhyay E, et al. Mechanosensitive membrane domains regulate calcium entry in arterial endothelial cells to protect against inflammation. J Clin Invest. 2024;134(13). https://doiorg.publicaciones.saludcastillayleon.es/10.1172/jci175057.

  39. Wang S, Chennupati R, Kaur H, Iring A, Wettschureck N, Offermanns S. Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release. J Clin Invest. 2016;126(12):4527–36. https://doiorg.publicaciones.saludcastillayleon.es/10.1172/jci87343.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sonkusare SK, Dalsgaard T, Bonev AD, Hill-Eubanks DC, Kotlikoff MI, Scott JD, et al. AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. Sci Signal. 2014;7(333):ra66. https://doiorg.publicaciones.saludcastillayleon.es/10.1126/scisignal.2005052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Longden TA, Nelson MT. Vascular inward rectifier K+ channels as external K+ sensors in the control of cerebral blood flow. Microcirculation. 2015;22(3):183–96. https://doiorg.publicaciones.saludcastillayleon.es/10.1111/micc.12190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Büssemaker E, Wallner C, Fisslthaler B, Fleming I. The Na-K-ATPase is a target for an EDHF displaying characteristics similar to potassium ions in the porcine renal interlobar artery. Br J Pharmacol. 2002;137(5):647–54. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/sj.bjp.0704919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pesic A, Madden JA, Pesic M, Rusch NJ. High blood pressure upregulates arterial L-type Ca2+ channels: is membrane depolarization the signal? Circ Res. 2004;94(10):e97-104. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.RES.0000131495.93500.3c.

    Article  CAS  PubMed  Google Scholar 

  44. Narayanan D, Xi Q, Pfeffer LM, Jaggar JH. Mitochondria control functional CaV1.2 expression in smooth muscle cells of cerebral arteries. Circ Res. 2010;107(5):631–41. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circresaha.110.224345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. DuPont JJ, McCurley A, Davel AP, McCarthy J, Bender SB, Hong K, et al. Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging. JCI Insight. 2016;1(14): e88942. https://doiorg.publicaciones.saludcastillayleon.es/10.1172/jci.insight.88942.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Navedo MF, Nieves-Cintron M, Amberg GC, Yuan C, Votaw VS, Lederer WJ, et al. AKAP150 is required for stuttering persistent Ca2+ sparklets and angiotensin II-induced hypertension. Circ Res. 2008;102(2):e1–11. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCRESAHA.107.167809.

  47. Flores-Tamez VA, Martín-Aragón Baudel M, Hong J, Taylor JL, Ren L, Le T, et al. α1C S1928 phosphorylation of Cav1.2 channel controls vascular reactivity and blood pressure. J Am Heart Assoc. 2024;13(20):e035375. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/jaha.124.035375.

    Article  PubMed  Google Scholar 

  48. Nieves-Cintron M, Amberg GC, Navedo MF, Molkentin JD, Santana LF. The control of Ca2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension. Proc Natl Acad Sci U S A. 2008;105(40):15623–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1073/pnas.0808759105.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Nieves-Cintron M, Amberg GC, Nichols CB, Molkentin JD, Santana LF. Activation of NFATc3 down-regulates the β1 subunit of large conductance, calcium-activated K+ channels in arterial smooth muscle and contributes to hypertension. J Biol Chem. 2007;282(5):3231–40. https://doiorg.publicaciones.saludcastillayleon.es/10.1074/jbc.M608822200.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang Y, Xu Z, Shan M, Cao J, Zhou Y, Chen Y, et al. Arterial smooth muscle cell AKAP150 mediates exercise-induced repression of CaV1.2 channel function in cerebral arteries of hypertensive rats. Arterioscler Thromb Vasc Biol. 2024;44(6):1202–21. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/atvbaha.124.319543.

    Article  CAS  PubMed  Google Scholar 

  51. Retailleau K, Duprat F, Arhatte M, Ranade SS, Peyronnet R, Martins JR, et al. Piezo1 in smooth muscle cells is involved in hypertension-dependent arterial remodeling. Cell Rep. 2015;13(6):1161–71. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.celrep.2015.09.072.

    Article  CAS  PubMed  Google Scholar 

  52. Abou-Saleh H, Pathan AR, Daalis A, Hubrack S, Abou-Jassoum H, Al-Naeimi H, et al. Inositol 1,4,5-trisphosphate (IP3) receptor up-regulation in hypertension is associated with sensitization of Ca2+ release and vascular smooth muscle contractility. J Biol Chem. 2013;288(46):32941–51. https://doiorg.publicaciones.saludcastillayleon.es/10.1074/jbc.m113.496802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schleifenbaum J, Kassmann M, Szijártó IA, Hercule HC, Tano J-Y, Weinert S, et al. Stretch-activation of angiotensin II type 1a receptors contributes to the myogenic response of mouse mesenteric and renal arteries. Circ Res. 2014;115(2):263–72. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circresaha.115.302882.

    Article  CAS  PubMed  Google Scholar 

  54. Brenner R, Perez GJ, Bonev AD, Eckman DM, Kosek JC, Wiler SW, et al. Vasoregulation by the β1 subunit of the calcium-activated potassium channel. Nature. 2000;407(6806):870–6. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/35038011.

    Article  CAS  PubMed  Google Scholar 

  55. Leo MD, Zhai X, Yin W, Jaggar JH. Impaired trafficking of β1 subunits inhibits BK channels in cerebral arteries of hypertensive rats. Hypertension. 2018;72(3):765–75. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/hypertensionaha.118.11147.

    Article  CAS  PubMed  Google Scholar 

  56. Taylor JL, Walsh KR, Mosneag IE, Danby TGE, Luka N, Chanda B, et al. Uncoupling of Ca2+ sparks from BK channels in cerebral arteries underlies hypoperfusion in hypertension-induced vascular dementia. Proc Natl Acad Sci U S A. 2023;120(33): e2307513120. https://doiorg.publicaciones.saludcastillayleon.es/10.1073/pnas.2307513120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Förstermann U, Li H. Therapeutic effect of enhancing endothelial nitric oxide synthase (eNOS) expression and preventing eNOS uncoupling. Br J Pharmacol. 2011;164(2):213–23. https://doiorg.publicaciones.saludcastillayleon.es/10.1111/j.1476-5381.2010.01196.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mao A, Zhang P, Zhang K, Kan H, He D, Han X, et al. Endothelial TRPV4-eNOS coupling as a vital therapy target for treatment of hypertension. Br J Pharmacol. 2022;179(10):2297–312. https://doiorg.publicaciones.saludcastillayleon.es/10.1111/bph.15755.

    Article  CAS  PubMed  Google Scholar 

  59. Albarrán-Juárez J, Iring A, Wang S, Joseph S, Grimm M, Strilic B, et al. Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation. J Exp Med. 2018;215(10):2655–72. https://doiorg.publicaciones.saludcastillayleon.es/10.1084/jem.20180483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Swain SM, Liddle RA. Piezo1 acts upstream of TRPV4 to induce pathological changes in endothelial cells due to shear stress. J Biol Chem. 2021;296:100171. https://doiorg.publicaciones.saludcastillayleon.es/10.1074/jbc.ra120.015059.

    Article  CAS  PubMed  Google Scholar 

  61. Wilson C, Zhang X, Buckley C, Heathcote HR, Lee MD, McCarron JG. Increased vascular contractility in hypertension results from impaired endothelial calcium signaling. Hypertension. 2019;74(5):1200–14. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/HYPERTENSIONAHA.119.13791.

    Article  CAS  PubMed  Google Scholar 

  62. Ottolini M, Hong K, Cope EL, Daneva Z, DeLalio LJ, Sokolowski JD, et al. Local peroxynitrite impairs endothelial transient receptor potential vanilloid 4 channels and elevates blood pressure in obesity. Circulation. 2020;141(16):1318–33. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circulationaha.119.043385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Koide M, Harraz OF, Dabertrand F, Longden TA, Ferris HR, Wellman GC, et al. Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease. J Clin Invest. 2021;131(18). https://doiorg.publicaciones.saludcastillayleon.es/10.1172/jci149029.

  64. Sun HJ, Ren XS, Xiong XQ, Chen YZ, Zhao MX, Wang JJ, et al. NLRP3 inflammasome activation contributes to VSMC phenotypic transformation and proliferation in hypertension. Cell Death Dis. 2017;8(10):e3074. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/cddis.2017.470.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Nolze A, Matern S, Grossmann C. Calcineurin is a universal regulator of vessel function—focus on vascular smooth muscle cells. Cells. 2023;12(18):2269. https://doiorg.publicaciones.saludcastillayleon.es/10.3390/cells12182269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Reyes Gaido OE, Nkashama LJ, Schole KL, Wang Q, Umapathi P, Mesubi OO, et al. CaMKII as a therapeutic target in cardiovascular disease. Annu Rev Pharmacol Toxicol. 2023;63(1):249–72. https://doiorg.publicaciones.saludcastillayleon.es/10.1146/annurev-pharmtox-051421-111814.

    Article  CAS  PubMed  Google Scholar 

  67. Nishida M, Tanaka T, Mangmool S, Nishiyama K, Nishimura A. Canonical transient receptor potential channels and vascular smooth muscle cell plasticity. J Lipid Atheroscler. 2020;9(1):124–39. https://doiorg.publicaciones.saludcastillayleon.es/10.12997/jla.2020.9.1.124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Johnson M, Trebak M. ORAI channels in cellular remodeling of cardiorespiratory disease. Cell Calcium. 2019;79:1–10. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.ceca.2019.01.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bush E, Maeda N, Kuziel WA, Dawson TC, Wilcox JN, DeLeon H, et al. CC chemokine receptor 2 is required for macrophage infiltration and vascular hypertrophy in angiotensin II-induced hypertension. Hypertension. 2000;36(3):360–3. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.hyp.36.3.360.

    Article  CAS  PubMed  Google Scholar 

  70. Wenzel P, Knorr M, Kossmann S, Stratmann J, Hausding M, Schuhmacher S, et al. Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction. Circulation. 2011;124(12):1370–81. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCULATIONAHA.111.034470.

    Article  CAS  PubMed  Google Scholar 

  71. Moore JP, Vinh A, Tuck KL, Sakkal S, Krishnan SM, Chan CT, et al. M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss, and elevated blood pressure. Am J Physiol Heart Circ Physiol. 2015;309(5):H906–17. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/ajpheart.00821.2014.

    Article  CAS  PubMed  Google Scholar 

  72. Wójtowicz A, Babu SS, Li L, Gretz N, Hecker M, Cattaruzza M. Zyxin mediation of stretch-induced gene expression in human endothelial cells. Circ Res. 2010;107(7):898–902. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circresaha.110.227850.

    Article  PubMed  Google Scholar 

  73. Cattaruzza M, Lattrich C, Hecker M. Focal adhesion protein Zyxin is a mechanosensitive modulator of gene expression in vascular smooth muscle cells. Hypertension. 2004;43(4):726–30. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.hyp.0000119189.82659.52.

    Article  CAS  PubMed  Google Scholar 

  74. Tieu BC, Lee C, Sun H, Lejeune W, Recinos A 3rd, Ju X, et al. An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. J Clin Invest. 2009;119(12):3637–51. https://doiorg.publicaciones.saludcastillayleon.es/10.1172/JCI38308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang L, Zhao X-C, Cui W, Ma Y-Q, Ren H-L, Zhou X, et al. Genetic and pharmacologic inhibition of the chemokine receptor CXCR2 prevents experimental hypertension and vascular dysfunction. Circulation. 2016;134(18):1353–68. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circulationaha.115.020754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Rodríguez-Iturbe B, Pons H, Quiroz Y, Gordon K, Rincón J, Chávez M, et al. Mycophenolate mofetil prevents salt-sensitive hypertension resulting from angiotensin II exposure. Kidney Int. 2001;59(6):2222–32. https://doiorg.publicaciones.saludcastillayleon.es/10.1046/j.1523-1755.2001.00737.x.

    Article  PubMed  Google Scholar 

  77. Vinh A, Chen W, Blinder Y, Weiss D, Taylor WR, Goronzy JJ, et al. Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension. Circulation. 2010;122(24):2529–37. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circulationaha.109.930446.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Trott DW, Thabet SR, Kirabo A, Saleh MA, Itani H, Norlander AE, et al. Oligoclonal CD8+ T cells play a critical role in the development of hypertension. Hypertension. 2014;64(5):1108–15. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/HYPERTENSIONAHA.114.04147.

    Article  CAS  PubMed  Google Scholar 

  79. Mikolajczyk TP, Nosalski R, Szczepaniak P, Budzyn K, Osmenda G, Skiba D, et al. Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension. FASEB J. 2016;30(5):1987–99. https://doiorg.publicaciones.saludcastillayleon.es/10.1096/fj.201500088R.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Madhur MS, Lob HE, McCann LA, Iwakura Y, Blinder Y, Guzik TJ, et al. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension. 2010;55(2):500–7. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/HYPERTENSIONAHA.109.145094.

    Article  CAS  PubMed  Google Scholar 

  81. Lori A, Perrotta M, Lembo G, Carnevale D. The spleen: a hub connecting nervous and immune systems in cardiovascular and metabolic diseases. Int J Mol Sci. 2017;18(6):1216. https://doiorg.publicaciones.saludcastillayleon.es/10.3390/ijms18061216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lemarié CA, Tharaux PL, Esposito B, Tedgui A, Lehoux S. Transforming growth factor-alpha mediates nuclear factor kappaB activation in strained arteries. Circ Res. 2006;99(4):434–41. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.res.0000237388.89261.47.

    Article  PubMed  Google Scholar 

  83. Riou S, Mees B, Esposito B, Merval R, Vilar J, Stengel D, et al. High pressure promotes monocyte adhesion to the vascular wall. Circ Res. 2007;100(8):1226–33. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.RES.0000265231.59354.2c.

    Article  CAS  PubMed  Google Scholar 

  84. Flamant M, Placier S, Dubroca C, Esposito B, Lopes I, Chatziantoniou C, et al. Role of matrix metalloproteinases in early hypertensive vascular remodeling. Hypertension. 2007;50(1):212–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/HYPERTENSIONAHA.107.089631.

    Article  CAS  PubMed  Google Scholar 

  85. Hollestelle SCG, De Vries MR, Van Keulen JK, Schoneveld AH, Vink A, Strijder CF, et al. Toll-like receptor 4 is involved in outward arterial remodeling. Circulation. 2004;109(3):393–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.cir.0000109140.51366.72.

    Article  CAS  PubMed  Google Scholar 

  86. Galis ZS, Johnson C, Godin D, Magid R, Shipley JM, Senior RM, et al. Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ Res. 2002;91(9):852–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/01.res.0000041036.86977.14.

    Article  CAS  PubMed  Google Scholar 

  87. Suzuki Y, Kurata T, Koide T, Okada I, Nakajima N, Imaizumi Y, et al. Local Ca2+ signals within caveolae cause nuclear translocation of CaMK1α in mouse vascular smooth muscle cells. Biol Pharm Bull. 2022;45(9):1354–63. https://doiorg.publicaciones.saludcastillayleon.es/10.1248/bpb.b22-00319.

    Article  CAS  PubMed  Google Scholar 

  88. Suzuki Y, Ozawa T, Kurata T, Nakajima N, Zamponi GW, Giles WR, et al. A molecular complex of Cav1.2/CaMKK2/CaMK1a in caveolae is responsible for vascular remodeling via excitation-transcription coupling. Proc Natl Acad Sci U S A. 2022;119(16):e2117435119. https://doiorg.publicaciones.saludcastillayleon.es/10.1073/pnas.2117435119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wang Y, Liu Z, Song S, Wang J, Jin C, Jia L, et al. IRF5 governs macrophage adventitial infiltration to fuel abdominal aortic aneurysm formation. JCI Insight. 2024;9(3). https://doiorg.publicaciones.saludcastillayleon.es/10.1172/jci.insight.171488.

  90. Yamamura A, Fujiwara M, Kawade A, Amano T, Hossain A, Nayeem MJ, et al. Corosolic acid attenuates platelet-derived growth factor signaling in macrophages and smooth muscle cells of pulmonary arterial hypertension. Eur J Pharmacol. 2024;973: 176564. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.ejphar.2024.176564.

    Article  CAS  PubMed  Google Scholar 

  91. Tellides G, Pober JS. Inflammatory and immune responses in the arterial media. Circ Res. 2015;116(2):312–22. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCRESAHA.116.301312.

    Article  CAS  PubMed  Google Scholar 

  92. Goriely AR, Baldwin AL, Secomb TW. Transient diffusion of albumin in aortic walls: effects of binding to medial elastin layers. Am J Physiol Heart Circ Physiol. 2007;292(5):H2195–201. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/ajpheart.01294.2006.

    Article  CAS  PubMed  Google Scholar 

  93. Lutgens E, Atzler D, Döring Y, Duchene J, Steffens S, Weber C. Immunotherapy for cardiovascular disease. Eur Heart J. 2019;40(48):3937–46. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/eurheartj/ehz283.

    Article  CAS  PubMed  Google Scholar 

  94. Forrester SJ, Elliott KJ, Kawai T, Obama T, Boyer MJ, Preston KJ, et al. Caveolin-1 deletion prevents hypertensive vascular remodeling induced by angiotensin II. Hypertension. 2017;69(1):79–86. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/HYPERTENSIONAHA.116.08278.

    Article  CAS  PubMed  Google Scholar 

  95. Ramírez CM, Zhang X, Bandyopadhyay C, Rotllan N, Sugiyama MG, Aryal B, et al. Caveolin-1 regulates atherogenesis by attenuating low-density lipoprotein transcytosis and vascular inflammation independently of endothelial nitric oxide synthase activation. Circulation. 2019;140(3):225–39. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circulationaha.118.038571.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Zhang J, Nathan, Mehul, Norah, Wu M, Alicia, et al. Interleukin-1 Receptor Activation Potentiates Salt Reabsorption in Angiotensin II-Induced Hypertension via the NKCC2 Co-transporter in the Nephron. Cell Metabolism. 2016;23(2):360–8. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/j.cmet.2015.11.013.

  97. Sawai Y, Suzuki Y, Asagiri M, Hida S, Kondo R, Zamponi GW, et al. Caveolin-1 forms a complex with P2X7 receptor and tunes P2X7-mediated ATP signaling in mouse bone marrow-derived macrophages. Am J Physiol Cell Physiol. 2024;326(1):C125–42. https://doiorg.publicaciones.saludcastillayleon.es/10.1152/ajpcell.00303.2023.

    Article  PubMed  Google Scholar 

  98. Madhur MS, Elijovich F, Alexander MR, Pitzer A, Ishimwe J, Van Beusecum JP, et al. Hypertension: do inflammation and immunity hold the key to solving this epidemic? Circ Res. 2021;128(7):908–33. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/CIRCRESAHA.121.318052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Blacher J, Evans A, Arveiler D, Amouyel P, Ferrières J, Bingham A, et al. Residual cardiovascular risk in treated hypertension and hyperlipidaemia: the PRIME Study. J Hum Hypertens. 2010;24(1):19–26. https://doiorg.publicaciones.saludcastillayleon.es/10.1038/jhh.2009.34.

    Article  CAS  PubMed  Google Scholar 

  100. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–31. https://doiorg.publicaciones.saludcastillayleon.es/10.1056/NEJMoa1707914.

    Article  CAS  PubMed  Google Scholar 

  101. Zhao YY, Liu Y, Stan RV, Fan L, Gu Y, Dalton N, et al. Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc Natl Acad Sci U S A. 2002;99(17):11375–80. https://doiorg.publicaciones.saludcastillayleon.es/10.1073/pnas.172360799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Gratton J-P, Lin MI, Yu J, Weiss ED, Jiang ZL, Fairchild TA, et al. Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice. Cancer Cell. 2003;4(1):31–9. https://doiorg.publicaciones.saludcastillayleon.es/10.1016/s1535-6108(03)00168-5.

    Article  CAS  PubMed  Google Scholar 

  103. Jiang Y, Lin X, Tang Z, Lee C, Tian G, Du Y, et al. Critical role of caveolin-1 in ocular neovascularization and multitargeted antiangiogenic effects of cavtratin via JNK. Proc Natl Acad Sci U S A. 2017;114(40):10737–42. https://doiorg.publicaciones.saludcastillayleon.es/10.1073/pnas.1706394114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bernatchez P, Sharma A, Bauer PM, Marin E, Sessa WC. A noninhibitory mutant of the caveolin-1 scaffolding domain enhances eNOS-derived NO synthesis and vasodilation in mice. J Clin Invest. 2011;121(9):3747–55. https://doiorg.publicaciones.saludcastillayleon.es/10.1172/jci44778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Makarewich CA, Correll RN, Gao H, Zhang H, Yang B, Berretta RM, et al. A caveolae-targeted L-type Ca2+ channel antagonist inhibits hypertrophic signaling without reducing cardiac contractility. Circ Res. 2012;110(5):669–74. https://doiorg.publicaciones.saludcastillayleon.es/10.1161/circresaha.111.264028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Correll RN, Makarewich CA, Zhang H, Zhang C, Sargent MA, York AJ, et al. Caveolae-localized L-type Ca2+ channels do not contribute to function or hypertrophic signalling in the mouse heart. Cardiovasc Res. 2017;113(7):749–59. https://doiorg.publicaciones.saludcastillayleon.es/10.1093/cvr/cvx046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Figures were created with BioRender.com.

Funding

This work was supported by the Japan Society for the Promotion of Science KAKENHI Grants 23KK0308, 23K24036, 22H02773, 21K19343, 19H03381, 16H06215, and 16K15127 (to Y.S.), 23K14414 (to R.K.), 23K24049 and 22H02787 (to H.Y.), and 18KK0218 (to Y.I.). We also acknowledge the financial support provided by Grants-in-Aid from the Pharmacological Research Foundation, Suzuken Memorial Foundation, Japan Foundation for Applied Enzymology, Takeda Science Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Nakatomi Foundation, and the Hori Science and Arts Foundation (to Y. S.).

Author information

Authors and Affiliations

  1. Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, 467-8603, Japan

    Yoshiaki Suzuki, Rubii Kondo, Yuji Imaizumi & Hisao Yamamura

  2. Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada

    Wayne R. Giles

  3. Department of Clinical Neurosciences, Hotchkiss Brain Institute, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada

    Gerald W. Zamponi

Authors
  1. Yoshiaki Suzuki
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Wayne R. Giles
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Gerald W. Zamponi
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Rubii Kondo
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Yuji Imaizumi
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Hisao Yamamura
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

YS had the lead role in original planning and writing the draft and created the figures. RK helped draft and arranged the manuscript. WRG, GWZ, YI and HY provided editorial input. All the authors have read and approved the final manuscript.

Corresponding author

Correspondence to Yoshiaki Suzuki.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suzuki, Y., Giles, W.R., Zamponi, G.W. et al. Ca2+ signaling in vascular smooth muscle and endothelial cells in blood vessel remodeling: a review. Inflamm Regener 44, 50 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s41232-024-00363-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s41232-024-00363-0

Keywords

Inflammation and Regeneration

ISSN: 1880-8190

Contact us