LAUSR

Background. Arteriogenesis is a process whereby collateral vessels remodel usually in response to increased blood flow and/or wall stress. Remodeling of collaterals can function as a natural bypass to alleviate ischemia during arterial occlusion. Here we used a genetic approach to investigate possible roles of tyrosine receptor c‐Kit in arteriogenesis. Methods. Mutant mice with loss of c‐Kit function (KitW/W‐v), and controls were subjected to hindlimb ischemia. Blood flow recovery was evaluated pre‐, post‐, and weekly after ischemia. Foot ischemic damage and function were assessed between days 1 to 14 post‐ischemia while collaterals remodeling were measured 28 days post‐ischemia. Both groups of mice also were subjected to wild type bone marrow cells transplantation 3 weeks before hindlimb ischemia to evaluate possible contributions of defective bone marrow c‐Kit expression on vascular recovery. Results. KitW/W‐v mice displayed impaired blood flow recovery, greater ischemic damage and foot dysfunction after ischemia compared to controls. KitW/W‐v mice also demonstrated impaired collateral remodeling consistent with flow recovery findings. Because arteriogenesis is a biological process that involves bone marrow‐derived cells, we investigated which source of c‐Kit signaling (bone marrow or vascular) plays a major role in arteriogenesis. KitW/W‐v mice transplanted with bone marrow wild type cells exhibited similar phenotype of impaired blood flow recovery, greater tissue ischemic damage and foot dysfunction as nontransplanted KitW/W‐v mice. Conclusion. This study provides evidence that c‐Kit signaling is required during arteriogenesis. Also, it strongly suggests a vascular role for c‐Kit signaling because rescue of systemic c‐Kit activity by bone marrow transplantation did not augment the functional recovery of KitW/W‐v mouse hindlimbs.