Anti-Angiogenic Actions of VEGF-A165b, an Inhibitory 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 the development of adipose tissue hypoxia, capillary rarefaction, inflammation, and metabolic dysregulation, but pathophysiological 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 paired subcutaneous and visceral adipose tissue in 40 obese subjects (BMI 45±8 kg/m2, age 45±11 yr) during bariatric surgery and characterized depot-specific adipose tissue angiogenic capacity using an established ex vivo assay. Visceral adipose tissue exhibited significantly blunted angiogenic growth compared to subcutaneous fat (p<0.001) which was associated with marked tissue up-regulation of VEGF-A165b (p=0.004). Extent of VEGF-A165b expression correlated negatively with angiogenic growth (r= -0.6, p=0.006). While recombinant VEGF-A165b significantly impaired angiogenesis, targeted inhibition of VEGF-A165b with neutralizing antibody stimulated fat pad neovascularization and restored VEGF receptor activation. Blood levels of VEGF-A165b were significantly higher in obese subjects compared to lean controls (p=0.02), and surgical weight loss induced a marked decline in serumVEGF-A165b (p=0.003).
Conclusions—We demonstrate that impaired adipose tissue angiogenesis is associated with over-expression of a novel anti-angiogenic factor VEGF-A165b that may play a pathogenic role in human adiposopathy. Moreover, systemic up-regulation of VEGF-A165b in circulating blood may have wider ranging implications beyond the adipose milieu. VEGF-A165b may represent a novel area of investigation to gain further understanding of mechanisms that modulate cardiometabolic consequences of obesity.
- Received December 11, 2013.
- Revision received June 3, 2014.
- Accepted July 3, 2014.