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. 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. Conclusion-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. Key Words: collateral circulation Ⅲ growth factors Ⅲ peripheral arterial disease Ⅲ peripheral vasculature Ⅲ vascular biology C ardiovascular diseases are still the leading cause of death in Western societies, with coronary artery disease being responsible for approximately 50% of this burden. However, the heart of human beings is not defenseless against a slowly occurring closure of artery vessels but responds by collateral arterial growth. This process, which has been termed arteriogenesis, takes place in virtually all organs of the body. It is fundamentally different from angiogenesis in that it relies on the growth of preexisting collateral arterioles and not on the sprouting of capillaries. Arteriogenesis is initiated by shear stress leading to an inflammatory microenvironment and to the activation of growth factor cascades that spur collateral vessel growth and not by hypoxia, which mainly triggers angiogenesis. 1 Furthermore, arteriogenesis is able to completely restore perfusion after occlusion of arteries, whereas angiogenesis improves the local blood supply only marginally, because far too many capillaries would be needed to replace a conducting artery. 2 The ability of arteriogenesis to restore normal blood flow has raised the hope of stimulating this process to combat vascular ischemic diseases. However, the complexity of the regulatory mechanisms driving arteriogenesis, which includes the interplay of different cell types and many growth factors and cytokines, has slowed down therapeutic applications.On the cellular level, arteriogenesis is characterized by dedifferentiation, proliferation, and migra...

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