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.
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Acknowledgements
This work was supported by grants from the Canadian Institutes of Health Research to JW (MOP57697, MOP69089 and MOP 123389), HL (MOP97829), ET (MOP14496) and JT (ISO106797). It was also funded by grants from the Heart and Stroke Foundation of Quebec, the Natural Sciences and Engineering Research Council of Canada (203906-2012), the Juvenile Diabetes Research Foundation (17-2013-440), the Fonds de recherche du Québec-Santé (Ag-06) and the J-Louis Lévesque Foundation to JW.
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Wang, Y., Hamet, P., Thorin, E. et al. Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk. Eur J Hum Genet 24, 1817–1825 (2016). https://doi.org/10.1038/ejhg.2016.105
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DOI: https://doi.org/10.1038/ejhg.2016.105
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