title: EPHB4 Protein Expression in Vascular Smooth Muscle Cells Regulates Their Contractility, and EPHB4 Deletion Leads to Hypotension in Mice.
abstract: EPH kinases are the largest family of receptor tyrosine kinases, and their ligands, ephrins (EFNs), are also cell surface molecules. This work presents evidence that EPHB4 on vascular smooth muscle cells (VSMCs) is involved in blood pressure regulation. We generated gene KO mice with smooth muscle cell-specific deletion of EPHB4. Male KO mice, but not female KO mice, were hypotensive. VSMCs from male KO mice showed reduced contractility when compared with their WT counterparts. Signaling both from EFNBs to EPHB4 (forward signaling) and from EPHB4 to EFNB2 (reverse signaling) modulated VSMC contractility. At the molecular level, the absence of EPHB4 in VSMCs resulted in compromised signaling from Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to myosin light chain kinase (MLCK) to myosin light chain, the last of which controls the contraction force of motor molecule myosin. Near the cell membrane, an adaptor protein GRIP1, which can associate with EFNB2, was found to be essential in mediating EPHB4-to-EFNB reverse signaling, which regulated VSMC contractility, based on siRNA gene knockdown studies. Our research indicates that EPHB4 plays an essential role in regulating small artery contractility and blood pressure.
authors.affiliation: From the Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9.
authors.forename: Yujia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: the Montreal Heart Institute, Montreal, Quebec H1T 1C8.
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.affiliation: From the Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Luo
authors.affiliation: From the Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9.
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
authors.affiliation: From the Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9, the Département de Kinésiologie, Université de Montréal, Montreal, Quebec H3T 1J4, and.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Lavoie
authors.affiliation: From the Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9.
authors.forename: Zenghui
authors.initials: Z
authors.lastname: Wu
authors.affiliation: From the Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9.
authors.forename: Junzheng
authors.initials: J
authors.lastname: Peng
authors.affiliation: From the Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9.
authors.forename: Shijie
authors.initials: S
authors.lastname: Qi
authors.affiliation: From the Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2X 0A9, the Nephrology Service, CHUM, Montreal, Quebec H2L 4M1, Canada jianping.wu@umontreal.ca.
authors.forename: Jiangping
authors.initials: J
authors.lastname: Wu
mesh_terms: D000818:Animals; D001158:Arteries / Q000378:metabolism; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D007022:Hypotension / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D036224:Receptor, EphB4 / Q000502:physiology*; D012737:Sex Factors; D015398:Signal Transduction
chemical_list: D008024:Ligands; D034741:RNA, Small Interfering; C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4; D002118:Calcium
keywords: EPHB4 kinases; GRIP1; cell biology; gene knockout; hormone; hypertension; hypotension; sex hormones; vascular smooth muscle cells