Loss of c-Kit in Endothelial Cells Protects against Hindlimb Ischemia

TL;DR

Removing c-Kit in blood vessel cells improves blood flow and protects against leg ischemia in mice.

Contribution

This study reveals that endothelial c-Kit signaling negatively affects blood vessel formation and barrier integrity in ischemia.

Findings

Mice lacking endothelial c-Kit or SCF showed improved limb perfusion and arteriogenesis.

Endothelial barrier integrity was preserved in c-Kit and SCF knockout mice after aortic crush.

Lower c-Kit and SCF gene expression was confirmed in endothelial cells of knockout mice.

Abstract

Background: Critical limb ischemia (CLI) is the end stage of peripheral artery disease (PAD), and around 30% of CLI patients are ineligible for current treatments. The angiogenic benefits of c-Kit have been reported in the ischemia scenario; however, the present study demonstrates the effects of specific endothelial c-Kit signaling in arteriogenesis during hindlimb ischemia. Methods: We created conditional knockout mouse models that decrease c-Kit (c-Kit VE-Cadherin CreERT2—c-Kit) or its ligand (SCF VE-Cadherin CreERT2—SCF) specifically in endothelial cells (ECs) after tamoxifen treatment. These mice and a control group (wild-type VE-Cadherin CreERT2—WT) were subjected to hindlimb ischemia or aortic crush to evaluate perfusion/arteriogenesis and endothelial barrier permeability, respectively. Results: Our data confirmed the lower gene expression of c-Kit and SCF in the ECs of c-Kit and SCF mice, respectively. In addition, we confirmed the lower percentage of ECs positive for c-Kit in c-Kit mice. Further, we found that c-Kit and SCF mice had better limb perfusion and arteriogenesis compared to WT mice. We also demonstrated that c-Kit and SCF mice had a preserved endothelial barrier after aortic crush compared to WT. Conclusions: Our data demonstrate the deleterious effects of endothelial SCF/c-Kit signaling on arteriogenesis and endothelial barrier integrity.

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