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. 2018:2:29.
doi: 10.20517/2574-1209.2018.44. Epub 2018 Aug 30.

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

Derek Strassheim  1 , Vijaya Karoor  1   2 , Kurt Stenmark  2   3 , Alexander Verin  4 , Evgenia Gerasimovskaya  2   3
Affiliations

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

Derek Strassheim et al. Vessel Plus. 2018.

Abstract

Pathological vascular remodeling is observed in various cardiovascular diseases including pulmonary hypertension (PH), a disease of unknown etiology that has been characterized by pulmonary artery vasoconstriction, right ventricular hypertrophy, vascular inflammation, and abnormal angiogenesis in pulmonary circulation. G protein-coupled receptors (GPCRs) are the largest family in the genome and widely expressed in cardiovascular system. They regulate all aspects of PH pathophysiology and represent therapeutic targets. We overview GPCRs function in vasoconstriction, vasodilation, vascular inflammation-driven remodeling and describe signaling cross talk between GPCR, inflammatory cytokines, and growth factors. Overall, the goal of this review is to emphasize the importance of GPCRs as critical signal transducers and targets for drug development in PH.

Keywords: GPCR; Pulmonary hypertension; intracellular signaling; vascular inflammation; vascular remodeling; vasoconstriction.

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Conflict of interest statement

Conflicts of interest All authors declared that there are no conflicts of interest.

Figures

Figure 1.
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 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
Figure 2.
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
Figure 3.
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
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