Abstract
Introduction
C-kit is one of the most important tyrosine kinase receptors dynamically regulated in healthy and diseased blood vessels. However, whether c-Kit signaling is beneficial or detrimental to the vasculature remains elusive. This study assesses the impact of the loss of c-Kit in somatic and circulatory cells on atherosclerosis.
Methods and Results
c-Kit expression was abundant in human aortas as determined by RT-PCR, Western blot and immunofluorescence (IF) confocal microscopy. The vascular expression of this receptor varied among patients and tended to decrease in atherosclerotic arteries. Interestingly, in the murine aorta from a c-Kit reporter mouse, GFP was only found in a sub fraction of quiescent VSMC that reside just below the endothelium. c-Kit deficiency favored VSMC proliferation when aortic explants from c-Kit mutant (W/Wv) and wild type (WT) mice were simultaneously placed in a tissue culture system (cells per well: 1337 ± 167 vs. 696 ± 108, p= 0.0123). To measure the contribution of c-Kit signaling to atherosclerosis disease in ApoE KO mice, we fed ApoE KO mice carrying the c-Kit mutant alleles W and Wv with a high-cholesterol diet for 16 weeks. The atherosclerosis plaque burden in these mice was 2.5 greater than in control ApoE KO kit
+/+
mice (affected proportion of the aorta: 0.25 ± 0.03 vs.0.104 ± 0.01, p= 0.0002). Finally, we rescued lethally irradiated ApoE KO W/Wv and control ApoE KO kit
+/+
mice with ApoE KO kit
+/+
bone marrow (BM) cells to determine how the lack of c-Kit activity in BM-derived cells modifies atherosclerosis. While BM transplantation ameliorated most of the hematopoietic defects in the ApoE W/Wv recipients, it had little or no effect on preventing atherosclerotic disease development (affected proportion of the aorta: 0.09 ± 0.01 vs.0.05 ± 0.007, p= 0.03).
Conclusion
Our results demonstrate for the first time that somatic c-Kit-positive cells may confer protection against atherosclerosis in hyperlipidemic mice.