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Genetic Basis of Blood Pressure and Hypertension
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Sandosh Padmanabhan, Alisha Aman, Anna F. Dominiczak
Vascular endothelial function also modulates vascular tone. The vascular endothelium synthesizes and releases a spectrum of vasoactive substances, including NO, a potent vasodilator. NO exerts vasodilating and antiproliferative effects on smooth muscle cells and inhibits thrombocyte aggregation and leukocyte adhesion. The synthesis of NO is controlled by the enzyme endothelial NO synthase (NOS3) and is induced by calcium-mobilizing agents and fluid shear stress. Other vascular relaxation factors include endothelins and prostacyclin. Endothelin-1 (EDN1) activates specific ETA receptors (EDNRA) on vascular smooth muscle cells to cause vasoconstriction and cell proliferation. In contrast, endothelial ETB receptors (EDNRB) mediate vasodilatation via release of NO and prostacyclin (PGI2). GWAS of coronary artery disease (CAD) showed the SNP rs9349379 G allele (frequency 36%) was associated with increased risk of CAD and coronary calcification but decreased risk for four conditions (migraine headache, cervical artery dissection, fibromuscular dysplasia and HTN [89,90]). This SNP is located within the third intron of the gene encoding phosphatase and actin regulatory protein 1 (PHACTR1). However, functional analysis of this variant show that it regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The CAD risk associated with this allele is likely through increased endothelial production of ET-1 and subsequent binding to the ETA receptor, which promotes atherosclerosis. However, the association of the G allele with low systolic BP is thought to be through the action of ET-1 on the second endothelin receptor, ETB (91). In contrast to the coronary arteries where ETA receptors predominate, ETB receptors are more abundant in the large systemic arteries. The protective effect of this allele on BP is explained by action of ET1 on ETB receptors which predominate in large vessels. ET-1 binding to ETB triggers endothelium-dependent vasodilation through the production of NO, prostacyclins, and renal natriuresis. Interestingly, variants in the PHACTR1 gene have been associated with fibromuscular dysplasia (FMD), a nonatherosclerotic vascular disease leading to stenosis, dissection and aneurysm affecting mainly the renal and cerebrovascular arteries (92). Variants in the gene for vascular endothelial growth factor A (VEGFA) which induces proliferation, migration of vascular endothelial cells, and stimulates angiogenesis, is one of the replicated signals from GWAS. The GWAS locus containing urotensin-2 receptor (UTS2R) gene encodes a class A rhodopsin family G-protein—coupled receptor that upon activation by the neuropeptide urotensin II produces profound vasoconstriction. One of the GWAS loci is the relaxin gene, which encodes a G-protein—coupled receptor with roles in uterine relaxation, vasorelaxation and cardiac function which signals via phosphatidylinositol 3-kinase (PI3K).
2-{N-[(2,4,5-trichlorophenoxy) acetyl]-N-methylamino}-3-pyrrolidinepropanamide analogs as potential antagonists of Urotensin II receptor
Published in Journal of Receptors and Signal Transduction, 2023
Ajay Soni, Subham Saha, Aditi Agarwal, Abdul Rehman Abdul Rauf, Rakesh Kumar Singh, Mahesh Seth, Shashi Kant Singh, Sandeep Sinha, Raj Kumar Shirumalla, Shinji Marumoto, Ruchi Tandon
CHO-K1 cell lines over-expressing human and mouse Urotensin II receptor (UTS2R) having NCBI accession numbers NM_018949.1 and NM_145440.1 respectively were generated as reported previously [15,22,23]. Radio-iodinated human UII and UII peptide were procured from PerkinElmer Inc (Waltham, MA, USA) and GenScript, respectively. All other chemicals were purchased from Sigma-Aldrich Co. Compounds were dissolved in DMSO and further diluted in KHB buffer (1.2 mM KH2PO4, 4.2 mM NaHCO3, 1.2 mM MgSO4·7H2O, 118 mM NaCl, 4.7 mM KCl, 1.3 mM CaCl2, 11.7 mM D-Glucose, and 10 mM HEPES). Final DMSO concentration in all the cell-based assays was <0.5%.