EPHA4 regulates vascular smooth muscle cell contractility and is a sex-specific hypertension risk gene in individuals with type 2 diabetes

Abstract

This study investigated the association of genetic variants of EPHA4, a receptor tyrosine kinase, with hypertension, and the role of EPHA4 in vascular smooth muscle cell (VSMC) contractility. Methods: Data from two human genetic studies, ADVANCE and HCHS/SOL, were analysis for association of EPHA4 single nucleotide variants (SNVs) with hypertension risks. The effect of EPHA4 signalling and sex hormones on mouse vascular smooth muscle cells contractility was assessed. Results: We identified a single-nucleotide variant (rs75843691 hg19 chr2:g.222395371 C>G), located in the 3rd intron of EPHA4 gene, as significantly associated with hypertension in human female subjects (p-value = 8.3 x 10-4, below the Bonferroni-corrected critical p-value) but not male subjects with type 2 diabetes from the ADVANCE clinical trial. We found that EPHA4 was expressed in VSMCs and its stimulation by solid-phase anti-EPHA4 antibody led to reduced VSMC contractility triggered by phenylephrine. Estrogen enhanced the contractility-lowering effect of EPHA4 stimulation. Conversely, small interfering RNA knockdown of Epha4 expression in VSMCs resulted in increased contractility of VSMCs from female but not from male mice. Conclusion: EPHA4 is a sex-specific hypertension risk gene. Forward EPHA4 signalling reduces VSMC contractility, and estrogen is a modifier of this effect. The effect of EPHA4 on VSMCs contractility explains the association of EPHA4 gene with hypertension risks in females.

EPHB6 controls catecholamine biosynthesis by up-regulating tyrosine hydroxylase transcription in adrenal gland chromaffin cells

“…In all such cases, sex hormones act in concert with these EPHs/EFNs to control BP. Some of the findings from the mouse model have been corroborated by human genetic studies, in which we revealed that some variants in the EFNB2, EFNB3, and EPHA4 genes or a related signaling molecule gene are significantly associated with hypertension in a sex-specific way (19,21,22,24,25).EPHB6 is highly expressed in the medullae of adrenal glands, which are the major source of catecholamine (CAT) in the circulation. The ambient blood CAT level reflects this hormone's effect on the homeostasis of BP (26,27).…”

“…In the past 5 years, we have demonstrated in a series of publications (16 -25) that EPHs/EFNs are involved in regulating blood pressure (BP), which was previously unknown. We reported, using gene knockout mouse models, that although EPHB6, EFNB1, EFNB3, and EPHA4 deletion results in BP elevation (16,17,20,25), EPHB4 and EFNB2 deletion lowers it (18,19). Thus, members of EPHBs/ EFNBs are a novel yin and yang system that fine-tunes BP homeostasis.…”

Identification of Key Pathways and Genes in Polycystic Ovary Syndrome via Integrated Bioinformatics Analysis and Prediction of Small Therapeutic Molecules

“…Ostergaard et al [54], Zi et al [55], Kunej et al [56], Van der Schueren et al [57], Jin et al [58], Emdad et al [59], Liu et al [60], Scherag et al [61], Shi and Long [62], Sharma et al [63], Parente et al [64], Saint-Laurent et al [65] and Lee [66] demonstrated that over expression of COA3, PHB (prohibitin), UQCRC1, COX4I1, IFI27, MTDH (metadherin), S100A16, SDCCAG8, GLI2, NTN1, NLGN2, FGFR3 and PTPRN2 could cause obesity, but these genes might be involved in progression of PCOS. Alsters et al [67], Lee et al [68], Shiffman et al [69], Yaghootkar et al [70], Rotroff et al [71], Cheng et al [72], Baig et al [73], Zhang et al [74], Lebailly et al [75], Ferris et al [76], Lempainen et al [77] and McCallum et al [78] presented that high expression of CPE (carboxypeptidase E), RPL13A, CERS2, CCND2, PRPF31, SARM1, PLD1, EPHA4, ARNTL2, BATF3, IKZF4 and MEN1 were associated with diabetes, but these genes might be linked with advancement of PCOS. Wang et al [79], Tian et al [80], Zhang et al [81] and Carr et al [82] demonstrated that over expression of ATP6AP2, FIS1, GRK4 and KCNQ4 were found to be substantially related to hypertension, but these genes might be essential for PCOS progression.…”

Observational analyses from ADVANCE and ADVANCE‐ON

“…Several ADVANCE analyses have addressed genotypic associations with raised blood pressure [67][68][69][70] or kidney disease. 71,72 We have also identified the PROX1 gene CC genotype to be related to early-onset of diabetes.…”