title: Induction of smooth muscle cell migration during arteriogenesis is mediated by Rap2.
abstract: OBJECTIVE
  Collateral artery growth or arteriogenesis is the primary means of the circulatory system to maintain blood flow in the face of major arterial occlusions. Arteriogenesis depends on activation of fibroblast growth factor (FGF) receptors, but relatively little is known about downstream mediators of FGF signaling.
  
  
  RESULTS
  We screened for signaling components that are activated in response to administration of FGF-2 to cultured vascular smooth muscle cells (VSMCs) and detected a significant increase of Rap2 but not of other Ras family members, which corresponded to a strong upregulation of Rap2 and C-Raf in growing collaterals from rabbits with femoral artery occlusion. Small interfering RNAs directed against Rap2 did not affect FGF-2 induced proliferation of VSMC but strongly inhibited their migration. Inhibition of FGF receptor-1 (FGFR1) signaling by infusion of a sulfonic acid polymer or infection with a dominant-negative FGFR1 adenovirus inhibited Rap2 upregulation and collateral vessel growth. Similarly, expression of dominant-negative Rap2 blocked arteriogenesis, whereas constitutive active Rap2 enhanced collateral vessel growth.
  
  
  CONCLUSIONS
  Rap2 is part of the arteriogenic program and acts downstream of the FGFR1 to stimulate VSMC migration. Specific modulation of Rap2 might be an attractive target to manipulate VSMC migration, which plays a role in numerous pathological processes.
authors: Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors: Jochen
authors: J
authors: Pöling
authors: Marten
authors: M
authors: Szibor
authors: Silvia
authors: S
authors: Schimanski
authors: Marie-Elisabeth
authors: ME
authors: Ingelmann
authors: Wolfgang
authors: W
authors: Rees
authors: Praveen
authors: P
authors: Gajawada
authors: Zaber
authors: Z
authors: Kochfar
authors: Holger
authors: H
authors: Lörchner
authors: Isabelle
authors: I
authors: Salwig
authors: Jae-Young
authors: JY
authors: Shin
authors: Karsten
authors: K
authors: Wiebe
authors: Thomas
authors: T
authors: Kubin
authors: Henning
authors: H
authors: Warnecke
authors: Thomas
authors: T
authors: Braun
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement; D049109:Cell Proliferation; D003097:Collateral Circulation; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008026:Ligation; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D011817:Rabbits; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D012039:Regional Blood Flow; D013997:Time Factors; D014162:Transfection; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016222:Fibroblast Growth Factor 2; D051496:Receptor, Fibroblast Growth Factor, Type 1; C492137:Rap2a protein, mouse; D020668:rap GTP-Binding Proteins