Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

Yujia Wang, Pavel Hamet, Eric Thorin, Johanne Tremblay, John Raelson, Zenghui Wu, Hongyu Luo, Wei Jin, Julie L. Lavoie, Junzheng Peng, Francois Christophe Marois-Blanchet, Muhammad Ramzan Tahir, John Chalmers, Mark Woodward, Stephen Harrap, Shijie Qi, Charles Yibin Li, Jiangping Wu

Research output: Contribution to journalArticle

Abstract

Ephrin B2 (EFNB2) is a ligand for erythropoietin-producing hepatocellular kinases (EPH), the largest family of receptor tyrosine kinases. It has critical functions in many biological systems, but is not known to regulate blood pressure. We generated mice with a smooth muscle cell (SMC)-specific deletion of EFNB2 and investigated its roles in blood pressure regulation and vascular SMC (VSMC) contractility. Male Efnb2 knockout (KO) mice presented reduced blood pressure, whereas female KO mice had no such reduction. Both forward signaling from EFNB2 to EPHs and reverse signaling from EPHs to EFNB2 were involved in regulating VSMC contractility, with EPHB4 serving as a critical molecule for forward signaling, based on crosslinking studies. We also found that a region from aa 313 to aa 331 in the intracellular tail of EFNB2 was essential for reverse signaling regulating VSMC contractility, based on deletion mutation studies. In a human genetic study, we identified five SNPs in the 3′ region of the EFNB2 gene, which were in linkage disequilibrium and were significantly associated with hypertension for male but not female subjects, consistent with our findings in mice. The coding (minor) alleles of these five SNPs were protective in males. We have thus discovered a previously unknown blood pressure-lowering mechanism mediated by EFNB2 and identified EFNB2 as a gene associated with hypertension risk in humans.European Journal of Human Genetics advance online publication, 17 August 2016; doi:10.1038/ejhg.2016.105.

Original languageEnglish (US)
JournalEuropean Journal of Human Genetics
DOIs
StateAccepted/In press - Aug 17 2016
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Wang, Y., Hamet, P., Thorin, E., Tremblay, J., Raelson, J., Wu, Z., Luo, H., Jin, W., Lavoie, J. L., Peng, J., Marois-Blanchet, F. C., Tahir, M. R., Chalmers, J., Woodward, M., Harrap, S., Qi, S., Li, C. Y., & Wu, J. (Accepted/In press). Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk. European Journal of Human Genetics. https://doi.org/10.1038/ejhg.2016.105