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

Zeqin Zhang, Johanne Tremblay, John Raelson, Tamar Sofer, Lizhong Du, Qiang Fang, Maria Argos, Francois Christophe Marois-Blanchet, Yu Wang, Lingling Yan, John Chalmers, Mark Woodward, Stephen Harrap, Pavel Hamet, Hongyu Luo, Jiangping Wu

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Objective:We investigated the association of genetic variants of EPHA4, a receptor tyrosine kinase, with hypertension, and its role in vascular smooth muscle cell (VSMC) contractility.Methods:Data from two human genetic studies, ADVANCE and HCHS/SOL, were analyzed for association of EPHA4 single nucleotide variants (SNVs) with hypertension risks. The effect of EPHA4 signalling on mouse VSMC contractility was assessed.Results:We identified a SNV (rs75843691 hg19 chr2:g.222395371 C>G), located in the third intron of EPHA4 gene, being significantly associated with hypertension in human female patients (P value = 8.3 × 10-4, below the Bonferroni-corrected critical P value) but not male patients with type 2 diabetes from the ADVANCE clinical trial. We found that EPHA4 was expressed in VSMCs and its stimulation by anti-EPHA4 antibody led to reduced VSMC contractility. Estrogen enhanced the contractility-lowering effect of EPHA4 stimulation. Conversely, siRNA knockdown of Epha4 expression in VSMCs resulted in increased contractility of VSMCs from female mice but not from male mice.Conclusion:EPHA4 appears to be a sex-specific hypertension risk gene in type 2 diabetic patients. 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 female patients.

Original languageEnglish
Pages (from-to)775-789
Number of pages15
JournalJournal of Hypertension
Volume37
Issue number4
DOIs
Publication statusPublished - 1 Apr 2019
Externally publishedYes

Keywords

  • Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation
  • EPHA4
  • estrogen
  • gene variants
  • hypertension
  • single-nucleotide polymorphism
  • vascular smooth muscle cells

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    Zhang, Z., Tremblay, J., Raelson, J., Sofer, T., Du, L., Fang, Q., Argos, M., Marois-Blanchet, F. C., Wang, Y., Yan, L., Chalmers, J., Woodward, M., Harrap, S., Hamet, P., Luo, H., & Wu, J. (2019). EPHA4 regulates vascular smooth muscle cell contractility and is a sex-specific hypertension risk gene in individuals with type 2 diabetes. Journal of Hypertension, 37(4), 775-789. https://doi.org/10.1097/HJH.0000000000001948