title: Eph-B4 prevents venous adaptive remodeling in the adult arterial environment.
abstract: Eph-B4 determines mammalian venous differentiation in the embryo but is thought to be a quiescent marker of adult veins. We have previously shown that surgical transposition of a vein into the arterial environment is characterized by loss of venous identity, as indicated by the loss of Eph-B4, and intimal thickening. We used a mouse model of vein graft implantation to test the hypothesis that Eph-B4 is a critical determinant of venous wall thickness during postsurgical adaptation to the arterial environment. We show that stimulation of Eph-B4 signaling, either via ligand stimulation or expression of a constitutively active Eph-B4, inhibits venous wall thickening and preserves venous identity; conversely, reduction of Eph-B4 signaling is associated with increased venous wall thickness. Stimulated Eph-B4 associates with caveolin-1 (Cav-1); loss of Cav-1 or Eph-B4 kinase function abolishes inhibition of vein graft thickening. These results show that Eph-B4 is active in adult veins and regulates venous remodeling. Eph-B4-Cav-1-mediated vessel remodeling may be a venous-specific adaptive mechanism. Controlled stimulation of embryonic signaling pathways such as Eph-B4 may be a novel strategy to manipulate venous wall remodeling in adults.
authors.affiliation: Department of Surgery and 2 Department of Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Akihito
authors.initials: A
authors.lastname: Muto
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Harrison
authors.forename: Alberto
authors.initials: A
authors.lastname: Dávalos
authors.forename: Tiffany T
authors.initials: TT
authors.lastname: Fancher
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Ziegler
authors.forename: Amanda
authors.initials: A
authors.lastname: Feigel
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kondo
authors.forename: Toshiya
authors.initials: T
authors.lastname: Nishibe
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.forename: Alan
authors.initials: A
authors.lastname: Dardik
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D001158:Arteries / Q000502:physiology*; D051242:Caveolin 1 / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D051381:Rats; D036224:Receptor, EphB4 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014680:Veins / Q000502:physiology* / Q000637:transplantation
chemical_list: D051242:Caveolin 1; C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4