c-Kit Receptor Signaling Regulates Islet Vasculature, β-Cell Survival, and Function In Vivo

The receptor tyrosine kinase c-Kit plays an integral role in maintaining beta-cell mass and function. Although c-Kit receptor signaling promotes angiogenesis in multiple cell types, its role in islet vasculature is unknown. This study examines the effects of c-Kit-mediated vascular endothelial growth factor isoform A (VEGF-A) and islet vascularization on beta-cell function and survival using in vitro cell culture and in vivo mouse models. In cultured INS-1 cells and primary islets, c-Kit regulates VEGF-A expression via the Akt/mammalian target of rapamycin (mTOR) signaling pathway. Juvenile mice with mutated c-Kit (c-Kit(Wv/+)) showed impaired islet vasculature and beta-cell dysfunction, while restoring c-Kit expression in beta-cells of c-Kit(Wv/+) mice rescued islet vascular defects through modulation of the Akt/mTOR/VEGF-A pathway, indicating that c-Kit signaling in beta-cells is a required regulator for maintaining normal islet vasculature. Furthermore, beta-cell-specific c-Kit overexpression (c-Kit beta Tg) in aged mice showed significantly increased islet vasculature and beta-cell function, but, when exposed to a long-term high-fat diet, c-Kit signaling in c-Kit beta Tg mice induced substantial vascular remodeling, which resulted in increased islet inflammatory responses and beta-cell apoptosis. These results suggest that c-Kit-mediated VEGF-A action in beta-cells plays a pivotal role in maintaining islet vascularization and function.