1. Induction of smooth muscle cell migration during arteriogenesis is mediated by Rap2.
- Author
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Pöling J, Szibor M, Schimanski S, Ingelmann ME, Rees W, Gajawada P, Kochfar Z, Lörchner H, Salwig I, Shin JY, Wiebe K, Kubin T, Warnecke H, and Braun T
- Subjects
- Animals, Arterial Occlusive Diseases genetics, Arterial Occlusive Diseases pathology, Arterial Occlusive Diseases physiopathology, Cell Proliferation, Collateral Circulation, Disease Models, Animal, Femoral Artery metabolism, Femoral Artery pathology, Femoral Artery physiopathology, Femoral Artery surgery, Fibroblast Growth Factor 2 metabolism, HEK293 Cells, Humans, Ligation, Mice, Muscle, Smooth, Vascular pathology, Myocytes, Smooth Muscle pathology, RNA Interference, Rabbits, Receptor, Fibroblast Growth Factor, Type 1 metabolism, Regional Blood Flow, Time Factors, Transfection, rap GTP-Binding Proteins genetics, Arterial Occlusive Diseases metabolism, Cell Movement, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism, Neovascularization, Physiologic, rap GTP-Binding Proteins metabolism
- 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., Methods and 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.
- Published
- 2011
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