Activation of GPER Induces Differentiation and Inhibition of Coronary Artery Smooth Muscle Cell Proliferation

Abstract

BackgroundVascular pathology and dysfunction are direct life-threatening outcomes resulting from atherosclerosis or vascular injury, which are primarily attributed to contractile smooth muscle cells (SMCs) dedifferentiation and proliferation by re-entering cell cycle. Increasing evidence suggests potent protective effects of G-protein coupled estrogen receptor 1 (GPER) activation against cardiovascular diseases. However, the mechanism underlying GPER function remains poorly understood, especially if it plays a potential role in modulating coronary artery smooth muscle cells (CASMCs).Methodology/Principal FindingsThe objective of our study was to understand the functional role of GPER in CASMC proliferation and differentiation in coronary arteries using from humans and swine models. We found that the GPER agonist, G-1, inhibited both human and porcine CASMC proliferation in a concentration- (10−8 to 10−5 M) and time-dependent manner. Flow cytometry revealed that treatment with G-1 significantly decreased the proportion of S-phase and G2/M cells in the growing cell population, suggesting that G-1 inhibits cell proliferation by slowing progression of the cell cycle. Further, G-1-induced cell cycle retardation was associated with decreased expression of cyclin B, up-regulation of cyclin D1, and concomitant induction of p21, and partially mediated by suppressed ERK1/2 and Akt pathways. In addition, G-1 induces SMC differentiation evidenced by increased α-smooth muscle actin (α-actin) and smooth muscle protein 22α (SM22α) protein expressions and inhibits CASMC migration induced by growth medium.ConclusionGPER activation inhibits CASMC proliferation by suppressing cell cycle progression via inhibition of ERK1/2 and Akt phosphorylation. GPER may constitute a novel mechanism to suppress intimal migration and/or synthetic phenotype of VSMC.

Extent of Vascular Remodeling Is Dependent on the Balance Between Estrogen Receptor α and G-Protein–Coupled Estrogen Receptor

“…30 Our finding of the inhibitory effects of GPER activation on proliferation in rat aortic VSMCs is consistent with a previous report in coronary artery VSMCs. 57 Our finding that GPER activation inhibits migration has not previously been reported in VSMCs (nor has this been reported in any other noncancer cells). However, it is notable that in cancer cells, GPER activation has been shown to have cell-specific effects on migration-stimulating renal cell cancer cells migration 48 but inhibiting lung cancer cell migration.…”

Effects of estrogen on growth and smooth muscle differentiation of vascular wall-resident CD34+ stem/progenitor cells

“…However, current information about the effects of GPER M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 12 activation on vascular SMCs is much few and controversial [36,37,38]. We did not test this receptor because its expression was sharply decreased or barely detectable in cultured vascular SMCs and a GPER activation appeared only when the receptor was re-introdued [37,39,40].…”

Anti-Inflammatory Effects of Tanshinone IIA on Atherosclerostic Vessels of Ovariectomized ApoE-/- Mice are Mediated by Estrogen Receptor Activation and Through the ERK Signaling Pathway

“…Estrogen replacement therapy (ERT) and hormone replacement therapy (HRT) are now important issues for cardiovascular health in women. Although it has been proved that estrogen plays an important role as an anti-inflammation [3,4,5], antioxidation [6,7,8] agent, in human vascular smooth muscle cells (VSMC) [9,10,11], ERT and HRT can also lead to a series of adverse side effects, such as venous thrombosis, stroke, as well as cancers of the breast, uterus and ovaries [12,13,14,15]. Thus, the use of estrogenic therapy for the prevention of cardiovascular disease is still in debate.…”