ABSTRACT Vascular endothelial growth factor-A is a critical angiogenic factor that dramatically improves the vascularization in the obese adipose tissue, which thus protects transgenic mice not only against high-fat-diet-induced obesity but also insulin resistance. However, the precise mechanism underlining these metabolic benefits remains to be determined. Our preliminary results suggest that the function of vascular endothelial growth factor-A is associated with the upregulation of another angiogenic factor, angiopoietin-2. Moreover, Vascular endothelial growth factor-A stimulates sympathetic activation, enhancing lipolysis and energy expenditure in adipose tissue. This proposal is built upon these observations and the multitude of Vascular endothelial growth factor-A-related mouse models to dissect the complex physiological actions of this growth factor in adipose tissue. It is hypothesized that vascular endothelial growth factor-A synergistically interacts with angiopoietin-2 to form the functional new blood vessels in adipose tissue, promoting energy expenditure in a sympathetic activation- dependent manner. Specifically, two Aims are proposed: 1). To determine the role of angiopoietin-2 in vascular endothelial growth factor-A mediated angiogenesis in adipose tissue; 2). To investigate the mechanisms by which vascular endothelial growth factor-A-induced neuronal factors function on endothelial cells to improve angiogenesis in adipose tissue. The novel genetic models and pharmacological tools will be applied to achieve these Aims. Successful completion of the proposed studies will demonstrate the essential contribution of vascular endothelial growth factor-A to the dynamics of adipose tissue remodeling during both physiological (exercise and cold exposure) and pathological (obesity) conditions and highlight it as a factor with clinical significance in obesity and related diseases, which will provide insights for my independent R01 application.

PROJECT NARRATIVE Obesity, characterized by an excess of adipose tissue mass, is a major risk factor for many chronic diseases, including type 2 diabetes, cardiovascular disease, and hypertension. Results from our research will provide a better understanding of the molecular mechanism(s) by which vascular endothelial growth factor-A stimulates adipose tissue activity and hence brings about metabolic benefits which will further help to identify new strategies to treat obesity and related diseases.