4.7 Article

Novel Role of GPR35 (G-Protein-Coupled Receptor 35) in the Regulation of Endothelial Cell Function and Blood Pressure

期刊

HYPERTENSION
卷 78, 期 3, 页码 816-830

出版社

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.120.15423

关键词

blood pressure; cardiovascular diseases; GTP cyclohydrolase; homeostasis; nitric oxide

资金

  1. National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK109036, R01 DK119222]
  2. Department of VA [K6 BX005383, BX004663]
  3. National Eye Institute [EY022230]

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Inhibition of GPR35 was found to enhance endothelial cell functions and promote angiogenesis while reducing intracellular superoxide levels, resulting in improved vasodilation and decreased blood pressure in male mice. These findings suggest that antagonizing GPR35 activity could be a potential therapeutic approach to restore endothelial function and maintain hemodynamic homeostasis, particularly in the context of hypertension.
GPR35 (G-protein-coupled receptor 35) is a poorly characterized receptor that has garnered increased interest as a therapeutic target through its implications in a range of inflammatory and cardiovascular diseases, but its biological functions stay largely unknown. The current study evaluated the effect of GPR35 on endothelial cell (EC) functions and hemodynamic homeostasis. In primary human aortic ECs, the expression of GPR35 was manipulated by transfections of adenovirus carrying either GPR35 cDNA or shRNA against GPR35, using adenovirus carrying beta-gal as control. Mouse aortic ECs were isolated and cultured from GPR35 knockout and wild-type control mice. Our results indicated that genetic inhibition of GPR35 in human and mouse ECs significantly promoted cell proliferation, migration, and tube formation in vitro. The GCH1 (guanosine triphosphate cyclohydrolase I)-mediated biosynthesis of tetrahydrobiopterin was enhanced, reducing intracellular superoxide. Knocking down GCH1 or eNOS (endothelial nitric oxide synthase) significantly blunted the robust angiogenesis induced by GPR35 suppression. Male GPR35 knockout mice demonstrated reduced basal arterial blood pressure and an attenuated onset of hypertension in deoxycorticosterone acetate-salt induced hypertensive model compared with male GPR35 wild-type control mice in vivo, with concomitant improved endothelium-dependent vasodilation and decreased superoxide in isolated aortas. The difference in arterial blood pressure was absent between female GPR35 wild-type control and female GPR35 knockout mice. Our study provides novel insights into the roles of GPR35 in endothelial function and vascular tone modulation that critically contribute to the pathophysiology of blood pressure elevation. Antagonizing GPR35 activity might represent a potentially effective therapeutic approach to restore EC function and hemodynamic homeostasis.

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