C-KIT SIGNALING IN COLLATERALS REMODELING

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TITLE: C-KIT SIGNALING IN COLLATERALS REMODELING Critical limb ischemia (CLI) is the most advanced form of peripheral arterial disease. At the moment, endovascular procedures and bypass surgeries are the only effective treatments for limb revascularization. However, a significant proportion of CLI patients are not good candidates for these interventions, requiring primary amputation as the main treatment option. Therefore, an effective pharmacological strategy that prevents CLI and its devastating consequences represents a much- needed alternative for this patient population. Arteriogenesis is a physiological compensatory process in which pre-existing collaterals enlarge and serve as natural bypasses to severe occlusion of arteries. We have recently identified that the c-Kit receptor tyrosine kinase plays a key role in the remodeling of collaterals during arteriogenesis. We found that defective c-Kit function compromises blood flow recovery after hindlimb ischemia, which was not resolved with hematopoietic reconstitution of c-Kit activity. We have confirmed defective arteriogenesis in c-Kit mutant mice compared to controls. Mechanistically, we advanced our understanding of how the c-Kit/Kruppel-like factor 4 (KLF4) pathway orchestrates collateral remodeling. Therefore, our central hypothesis is that c-Kit/KLF-4 signaling controls the recovery of the smooth muscle cell (SMC) contractile phenotype at the maturation phase of arteriogenesis to prevent excessive remodeling and narrowing of collaterals. We propose two Specific Aims (SA) to test our hypothesis. In SA1, we will demonstrate the involvement of vascular c-Kit signaling in arteriogenesis. We will investigate whether inactivation or activation of c-Kit specifically in SMCs will lead to dysfunction or optimal arteriogenesis in unique transgenic models of loss- and gain- of-function of c-Kit, respectively. We will also identify molecular mechanisms that can be altered by the loss- or gain-of-function on SMC c-Kit. In SA2, we will dissect the molecular pathways upstream and downstream of c-Kit in SMCs. First, we will investigate whether cyclic strain dictates the oscillatory expression of the c-Kit receptor by activating protein kinase C, leading to c-Kit suppression. Next, we will determine whether c-Kit inhibits KLF4 through FBXO32-mediated ubiquitination, thereby restoring the contractile SMC phenotype and preventing defective remodeling. RELEVANCE: Approximately 80,000 major lower-extremity amputations occur in the United States every year due to CLI. In this study, we will identify novel therapeutic targets to improve arteriogenesis and prevent or alleviate the devastating effects of CLI. Moreover, we will identify the molecular mechanism that dictates phenotypic switching in SMCs, which may be applicable to the understanding and treatment of other vascular occlusive diseases.