Abstract 16076: Anti-Angiogenic Actions of Vegf-a165B, a Novel Isoform of Vegf-a, in Human Obesity
Background: Experimental studies suggest that visceral adiposity and adipose tissue dysfunction play a central role in obesity-related cardiometabolic complications. Impaired angiogenesis in fat has been implicated in mechanisms of adipose tissue hypoxia, capillary rarefaction, inflammation, and metabolic dysregulation, but mechanisms remain unknown. In this study, we examined the role of a novel anti-angiogenic isoform of vascular endothelial growth factor-A (VEGF-A), VEGF-A165b, in human obesity.
Methods and Results: We biopsied subcutaneous and visceral adipose tissue in 43 obese subjects (BMI 44± 2 kg/m2, age 43±2 yr) during planned bariatric surgery and characterized depot-specific adipose angiogenic capacity using an established ex vivo Matrigel assay. Visceral adipose tissue exhibited significantly blunted angiogenic growth compared to subcutaneous fat (p<0.001) which was associated with marked adipose tissue up-regulation of VEGF-A165b (p<0.05). Extent of VEGF-A165b expression correlated negatively with angiogenic growth (r2= 0.3, p=0.01). While recombinant VEGF-A165b significantly impaired angiogenesis, targeted inhibition of VEGF-A165b with neutralizing antibody stimulated fat pad neovascularization by restoring VEGFR-2 phosphorylation. Serum levels of VEGF-A165b were ~2-fold higher in obese subjects compared to lean controls (p=0.03), and surgical weight loss induced a marked decline in serumVEGF-A165b (p<0.01).
Conclusion: We demonstrate that impaired angiogenesis is associated with over-expression of a novel anti-angiogenic factor VEGF-A165b that may play a key pathogenic role in adipose vascular insufficiency. Importantly, the implications extend beyond the adipose milieu as increased circulating VEGF-A165b may adversely modulate vascular homeostasis in systemic targets such as coronary and peripheral circulations. VEGF-A165b may represent a novel area of targeted intervention in obesity-related vascular disease
- © 2013 by American Heart Association, Inc.