title: Estrogen and testosterone in concert with EFNB3 regulate vascular smooth muscle cell contractility and blood pressure.
abstract: EPH kinases and their ligands, ephrins (EFNs), have vital and diverse biological functions, although their function in blood pressure (BP) control has not been studied in detail. In the present study, we report that Efnb3 gene knockout (KO) led to increased BP in female but not male mice. Vascular smooth muscle cells (VSMCs) were target cells for EFNB3 function in BP regulation. The deletion of EFNB3 augmented contractility of VSMCs from female but not male KO mice, compared with their wild-type (WT) counterparts. Estrogen augmented VSMC contractility while testosterone reduced it in the absence of EFNB3, although these sex hormones had no effect on the contractility of VSMCs from WT mice. The effect of estrogen on KO VSMC contractility was via a nongenomic pathway involving GPER, while that of testosterone was likely via a genomic pathway, according to VSMC contractility assays and GPER knockdown assays. The sex hormone-dependent contraction phenotypes in KO VSMCs were reflected in BP in vivo. Ovariectomy rendered female KO mice normotensive. At the molecular level, EFNB3 KO in VSMCs resulted in reduced myosin light chain kinase phosphorylation, an event enhancing sensitivity to Ca(2+)flux in VSMCs. Our investigation has revealed previously unknown EFNB3 functions in BP regulation and show that EFNB3 might be a hypertension risk gene in certain individuals.
authors: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada;
authors: Yujia
authors: Y
authors: Wang
authors: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; jianping.wu@umontreal.ca.
authors: Zenghui
authors: Z
authors: Wu
authors: Montreal Heart Institute, Montreal, Quebec, Canada;
authors: Eric
authors: E
authors: Thorin
authors: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada;
authors: Johanne
authors: J
authors: Tremblay
authors: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Département de Kinésiologie, Université de Montréal, Montreal, Quebec, Canada;
authors: Julie L
authors: JL
authors: Lavoie
authors: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada;
authors: Hongyu
authors: H
authors: Luo
authors: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada;
authors: Junzheng
authors: J
authors: Peng
authors: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada;
authors: Shijie
authors: S
authors: Qi
authors: Institute of Cardiology, First Affiliated Hospital, Zhejiang University Medical College, Hangzhou, China; and.
authors: Tao
authors: T
authors: Wu
authors: Institute of Cardiology, First Affiliated Hospital, Zhejiang University Medical College, Hangzhou, China; and.
authors: Fei
authors: F
authors: Chen
authors: Institute of Cardiology, First Affiliated Hospital, Zhejiang University Medical College, Hangzhou, China; and.
authors: Jianzhong
authors: J
authors: Shen
authors: Institute of Cardiology, First Affiliated Hospital, Zhejiang University Medical College, Hangzhou, China; and.
authors: Shenjiang
authors: S
authors: Hu
authors: Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Nephrology Service, CRCHUM, Montreal, Quebec, Canada.
authors: Jiangping
authors: J
authors: Wu
mesh_terms: D000818:Animals; D001794:Blood Pressure; D036389:Ephrin-B3 / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000502:physiology; D013739:Testosterone / Q000378:metabolism*; D014661:Vasoconstriction
chemical_list: D036389:Ephrin-B3; D004967:Estrogens; D013739:Testosterone
keywords: blood pressure; ephrinb3; estrogen