Diabetes increases the risk and amplifies the severity of cerebral complications such as stroke and cognitive impairments. While it is known that diabetes impairs angiogenesis and neovascularization in the peripheral vascular beds, the lack of understanding of how diabetes affects brain vascular plasticity and integrity is a critical barrier to progress in the development of new strategies for prevention and treatment of these complications.Our long-term goal is to understand the pathways involved in the regulation of cerebrovascular structure and integrity to design better treatments for cerebrovascular complications in diabetes. The objective of this application is to define the role and mechanisms by which vascular endothelial growth factor (VEGF), a key angiogenic and permeability factor, regulates cerebral neovascularization in diabetes. We have compelling data that a) there is excessive neovascularization of the brain in the type 2 diabetic Goto-Kakizaki (GK) rats, b) newly formed vessels are immature, lack pericyte support and display increased permeability, c) VEGF-A and VEGF-R2 levels as well as VEGF-R2 signaling are up-regulated in the brain microvascular endothelial cells (BMVEC) isolated from these animals, d) roundabout-4 (Robo-4), an endothelial specific member of a group of axonal guidance proteins that stabilizes blood vessels, is decreased in BMVECs, e) inhibition of VEGF signaling increases Robo-4 expression and finally f) overexpression of Robo-4 in GK BMVECs decreases VEGF-induced migration. Our central hypothesis is that the uncoupling of the protective Robo-4/Slit-2 signaling by VEGF-A mediates pathological angiogenesis of the brain in diabetes.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||07/01/2014 → 06/30/2016|