title: Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis.
abstract: Bmx/Etk non-receptor tyrosine protein kinase has been implicated in endothelial cell migration and tube formation in vitro. However, the role of Bmx in vivo is not known. Bmx is highly induced in the vasculature of ischemic hind limbs. We used both mice with a genetic deletion of Bmx (Bmx-KO mice) and transgenic mice expressing a constitutively active form of Bmx under the endothelial Tie-2 enhancer/promoter (Bmx-SK-Tg mice) to study the role of Bmx in ischemia-mediated arteriogenesis/angiogenesis. In response to ischemia, Bmx-KO mice had markedly reduced, whereas Bmx-SK-Tg mice had enhanced, clinical recovery, limb perfusion, and ischemic reserve capacity when compared with nontransgenic control mice. The functional outcomes in these mice were correlated with ischemia-initiated arteriogenesis, capillary formation, and vessel maturation as well as Bmx-dependent expression/activation of TNF receptor 2- and VEGFR2-mediated (TNFR2/VEGFR2-mediated) angiogenic signaling in both hind limb and bone marrow. More importantly, results of bone marrow transplantation studies showed that Bmx in bone marrow-derived cells plays a critical role in the early phase of ischemic tissue remodeling. Our study provides the first demonstration to our knowledge that Bmx in endothelium and bone marrow plays a critical role in arteriogenesis/angiogenesis in vivo and suggests that Bmx may be a novel target for the treatment of vascular diseases such as coronary artery disease and peripheral arterial disease.
authors.affiliation: Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: He
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Shibo
authors.initials: S
authors.lastname: Tang
authors.forename: Iiro
authors.initials: I
authors.lastname: Rajantie
authors.forename: Petri
authors.initials: P
authors.lastname: Salven
authors.forename: Matthias
authors.initials: M
authors.lastname: Heil
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Dianhong
authors.initials: D
authors.lastname: Luo
authors.forename: Xianghong
authors.initials: X
authors.lastname: Li
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schaper
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Sinusas
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Wang
authors.initials: W
authors.lastname: Min
mesh_terms: D000818:Animals; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: C492367:BMX protein, human; C492366:Bmx protein, mouse; D011505:Protein-Tyrosine Kinases