Cover Picture: Schematic presentation of the mechanisms by which G protein-coupled receptors (GPCRs) regulate vascular tone and vascular smooth muscle cells (VSMC) proliferation. Vasoconstrictors like Ang II, ET1, thrombin, activate Gαi, Gαq, or G12/13-coupled GPCRs, increase Ca2+ via PLCβ activity, and receptor operated calcium channels such as TRPC6. Increase in PLCβ activity decreases PIP2 relieving tonic inhibition of TRPC6. Increase in Erk1/2 activity by Gi/Gq-coupled GPCRs activates TRPC6 by phosphorylation leading to increased Ca2+ entry and calmodulin-dependent protein kinase (CAMK) activation. CAMK increases MLCK activity by phosphorylation, which in turn phosphorylates MLC phosphorylation causing vasoconstriction. GPCRs coupled to G12/13 increase RhoA activity and the downstream kinase ROCK. ROCK increases MLC phosphorylation by inhibiting MLCP, or by direct phosphorylation. Vasodilators, such as PGI2 acting via Gs-coupled receptors activate PKA thereby inhibit Ca2+ increase by PKA-mediated phosphorylation of PLCβ and TRPC6. In ECs, Gi, or Gq-coupled GPCRs, increase, PI3K-Akt signaling and activate eNOS by phosphorylation at Ser1177. NO diffuses to nearby VSMC, activating soluble guanylate cyclase, increasing cGMP, activating PKG, and inhibiting TRPC6 by phosphorylation. PKG also activates the GAPs for Gq, RGS2 and RGS4 to inhibit PLCβ activity thereby attenuating Ca2+ entry. Both PKG- and PKA inhibit RhoA by direct phosphorylation and promote vasodilation.
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