Fig. 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. Ca_v1.2 channel functions as the main Ca²⁺-permeable channel. Stretch-sensitive ion channels, TRPM4/TRPC6, can activate Ca_v1.2 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 BK_Ca channels to induce STOCs and hyperpolarize the membrane potential. Caveolin1 and junctophilin2 are expressed in close proximity to RyR2 and BK_Ca channels. TRPV4 channels increase STOCs either by supplying Ca²⁺ directly to BK_Ca channels, or indirectly via Ca²⁺ sparks. K_v channels can hyperpolarize the membrane potential and suppress the activity of Ca_v1.2 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 IK_Ca channels and eNOS to produce EDHF and NO, respectively. K_ir2.1 channels amplify the hyperpolarization response by IK_Ca/SK_Ca 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 K_ir2.1 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