title: Possible role of Efnb1 protein, a ligand of Eph receptor tyrosine kinases, in modulating blood pressure.
abstract: Eph kinases constitute the largest receptor tyrosine kinase family, and their ligands, ephrins (Efns), are also cell surface molecules. Although they are ligands, Efns can transduce signals reversely into cells. We have no prior knowledge of the role played by any members of this family of kinases or their ligands in blood pressure (BP) regulation. In the present studies, we investigated the role of Efnb1 in vascular smooth muscle cell (VSMC) contractility and BP regulation. We revealed that reverse signaling through Efnb1 led to a reduction of RhoA activation and VSMC contractility in vitro. Consistent with this finding, ex vivo, there was an increase of RhoA activity accompanied by augmented myosin light chain phosphorylation in mesenteric arteries from mice with smooth muscle-specific conditional Efnb1 gene knock-out (KO). Small interfering RNA knockdown of Grip1, a molecule associated with the Efnb1 intracellular tail, partially eliminated the effect of Efnb1 on VSMC contractility and myosin light chain phosphorylation. In support of these in vitro and ex vivo results, Efnb1 KO mice on a high salt diet showed a statistically significant heightened increment of BP at multiple time points during stress compared with wild type littermates. Our results demonstrate that Efnb1 is a previously unknown negative regulator of VSMC contractility and BP and that it exerts such effects via reverse signaling through Grip1.
authors.affiliation: Nephrology Department, Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec H2L 4M1, Canada.
authors.forename: Zenghui
authors.initials: Z
authors.lastname: Wu
authors.forename: Hongyu
authors.initials: H
authors.lastname: Luo
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.forename: Johanne
authors.initials: J
authors.lastname: Tremblay
authors.forename: Junzheng
authors.initials: J
authors.lastname: Peng
authors.forename: Julie L
authors.initials: JL
authors.lastname: Lavoie
authors.forename: Yujia
authors.initials: Y
authors.lastname: Wang
authors.forename: Shijie
authors.initials: S
authors.lastname: Qi
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Jiangping
authors.initials: J
authors.lastname: Wu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D048429:Cell Size; D002478:Cells, Cultured; D036387:Ephrin-B1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D036081:Receptors, Eph Family / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014661:Vasoconstriction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C092571:Efnb1 protein, mouse; D036387:Ephrin-B1; C491309:Grip1 protein, mouse; D008024:Ligands; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins; D036081:Receptors, Eph Family; D002118:Calcium