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

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 endoth...

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Bibliographic Details
Published in:Biomedicines 2024-06, Vol.12 (6), p.1358
Main Authors: Falero-Diaz, Gustavo, Barboza, Catarina de A, Vazquez-Padron, Roberto I, Velazquez, Omaida C, Lassance-Soares, Roberta M
Format: Article
Language:English
Subjects:
Amputation
Angiogenesis
Animal models
Animals
Aorta
arteriogenesis
Atherosclerosis
c-Kit
Cadherins
CLI
Coronary vessels
Disease
endothelial barrier
Endothelial cells
Endothelium
Ethylenediaminetetraacetic acid
Females
Gene expression
Ischemia
Ketamine
Kinases
Limbs
Mortality
Perfusion
Permeability
SCF
Smooth muscle
Stem cell factor
Vascular diseases
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Summary: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. 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. 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. Our data demonstrate the deleterious effects of endothelial SCF/c-Kit signaling on arteriogenesis and endothelial barrier integrity.
ISSN:2227-9059
2227-9059
DOI:10.3390/biomedicines12061358