FIGURE 7.

Diagram of proposed model of how SVEP1 regulated GPCR‐mediated vasoconstriction. U46619 binds to TXA₂ receptors (TXA2R) to activate Gα_q and G_12/13 signalling. Gα_q activates PLCβ, which hydrolyses PIP₂ into DAG and IP₃. Binding of IP₃ to the IP₃ receptors (IP₃R) on the SR induces Ca²⁺ release from stores. DAG activated PKC promotes the opening of VGCCs to initiate Ca²⁺ influx into the cell. Ca²⁺‐bound CaM activates MLCK, which phosphorylates MLC leading to contraction. Activation of PKC and G_12/13 also activates ROCK, which inhibits MLCP, promoting further activation of MLC and contraction. SVEP1 regulates contractility of VSMC via integrins α4/α9 by interacting with both calcium‐dependent pathways that reduce PKC activity and the influx of extracellular Ca²⁺ through VGCCs, and calcium sensitisation via ROCK. Abbreviations: α4, integrin α4β1; α9, integrin α9β1; CaM, calmodulin; DAG, diacylglycerol; IP₃, inositol triphosphate; MLC(K)(P), myosin light chain (kinase)(phosphatase); PIP₂, phosphatidylinositol diphosphate; PKC, protein kinase C; PLCβ, phospholipase C β; ROCK, Rho A/Rho kinase; SR, sarcoplasmic reticulum; VGCCs, voltage gated calcium channels; VSMC, vascular smooth muscle cell