title: c-Kit Receptor Signaling Regulates Islet Vasculature, β-Cell Survival, and Function In Vivo.
abstract: The receptor tyrosine kinase c-Kit plays an integral role in maintaining β-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 β-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 β-cell dysfunction, while restoring c-Kit expression in β-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 β-cells is a required regulator for maintaining normal islet vasculature. Furthermore, β-cell-specific c-Kit overexpression (c-KitβTg) in aged mice showed significantly increased islet vasculature and β-cell function, but, when exposed to a long-term high-fat diet, c-Kit signaling in c-KitβTg mice induced substantial vascular remodeling, which resulted in increased islet inflammatory responses and β-cell apoptosis. These results suggest that c-Kit-mediated VEGF-A action in β-cells plays a pivotal role in maintaining islet vascularization and function.
authors.affiliation: Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Feng
authors.affiliation: Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Popell
authors.affiliation: Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Jinming
authors.initials: J
authors.lastname: Li
authors.affiliation: Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Jenna
authors.initials: J
authors.lastname: Silverstein
authors.affiliation: Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Pathology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Oakie
authors.affiliation: Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT.
authors.forename: Siu-Pok
authors.initials: SP
authors.lastname: Yee
authors.affiliation: Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada Department of Medicine, University of Western Ontario, London, Ontario, Canada rwang@uwo.ca.
authors.forename: Rennian
authors.initials: R
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D019009:Proto-Oncogene Proteins c-kit