A current view of G protein-coupled receptor - mediated signaling in pulmonary hypertension: finding opportunities for therapeutic intervention

Figures

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  Figure 1.. 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…

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  Figure 2.. Schematic diagram illustrating a role of PI3K, Rho and ROCK pathways in hypoxia-induced ATP release and ATP-mediated angiogenic effects in vasa vasorum endothelial cells. Activation of PI3K/Rho/ROCK pathway in response to hypoxia results in regulated ATP release from VVEC. In turn, extracellular ATP triggers/initiates P2YR-dependent activation of PI3K/Rho/ROCK pathway leading to angiogenic responses in vasa vasorum endothelial cells. VVEC: vasa vasorum endothelial cells

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  Figure 3.. Extracellular ATP up regulates HIF-1α and HIF-2α transcription factors in pulmonary artery vasa vasorum endothelial cells. A, B: ATP (10 μmol/L), applied to VVEC, results in activation of both HIF-1α and HIF-2α with distinct time courses. VVEC were serum starved for 18 h and stimulated for indicated times. Nuclear fractions were subjected for Western blot analysis for HIF-1α, HIF-2α, and lamin A/C expression; C: cells were stained for HIF-1α at 1 h post stimulation with ATP (10 μmol/L), with or without PI3K inhibitor, PI-103 pretreatment (0.5 μmol/L, 15 min). VVEC: vasa vasorum endothelial cells