title: Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk.
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.
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Pavel
authors.initials: P
authors.lastname: Hamet
authors.affiliation: Department of Surgery, Université de Montréal and Université Montreal Heart Institute, Montreal, QC, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.|PGX-Services, Montreal, QC, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Raelson
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Zenghui
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Luo
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.|Department of Kinesiology, University of Montreal, Montreal, QC, Canada.
authors.forename: Julie L
authors.identifier: 0000-0001-6316-2769
authors.initials: JL
authors.lastname: Lavoie
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Junzheng
authors.initials: J
authors.lastname: Peng
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Francois-Christophe
authors.initials: FC
authors.lastname: Marois-Blanchet
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Muhammad Ramzan
authors.initials: MR
authors.lastname: Tahir
authors.affiliation: Department of Biostatistics, The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Chalmers
authors.affiliation: Department of Biostatistics, The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Woodward
authors.affiliation: Department of Physiology, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Harrap
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Shijie
authors.initials: S
authors.lastname: Qi
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Charles Yibin
authors.initials: CY
authors.lastname: Li
authors.affiliation: Research Centre, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.|Department of Nephrology, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.
authors.forename: Jiangping
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D001794:Blood Pressure; D036388:Ephrin-B2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D000072417:Protein Domains; D012737:Sex Factors; D015398:Signal Transduction
chemical_list: C000601239:EFNB2 protein, human; C000601240:EFNB2 protein, mouse; D036388:Ephrin-B2