Loss of c-Kit function impairs arteriogenesis in a mouse model of hindlimb ischemia

Diana R. Hernandez, Adriana Artiles, Juan C. Duque, Laisel Martinez, Mariana T. Pinto, Keith A Webster, Omaida C Velazquez, Roberto I Vazquez-Padron, Roberta Soares

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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. (Surgery 2017;160:XXX-XXX.).

Original languageEnglish (US)
JournalSurgery (United States)
DOIs
StateAccepted/In press - Jan 1 2017

ASJC Scopus subject areas

  • Surgery

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