Experimental studies suggest that Wingless-related integration site 5a (WNT5A) is a pro-inflammatory secreted protein that is associated with metabolic dysfunction in obesity. Impaired angiogenesis in fat has been implicated in the development of adipose tissue capillary rarefaction, hypoxia, inflammation and metabolic dysfunction. We recently demonstrated that impaired adipose tissue angiogenesis is associated with overexpression of anti-angiogenic factor VEGF-A165b in human fat and the systemic circulation. In the present study, we postulated that up-regulation of WNT5A is associated with angiogenic dysfunction and examined its role in regulating VEGF165b expression in human obesity. We biopsied subcutaneous and visceral adipose tissue from 38 obese individuals during planned bariatric surgery and characterized depot-specific protein expression of VEGF-A165b and WNT5A using Western blot analysis. In both subcutaneous and visceral fat, VEGF-A165b expression correlated strongly with WNT5A protein (r =0.9, p<0.001). In subcutaneous adipose tissue where angiogenic capacity is greater than in the visceral depot, exogenous human recombinant WNT5A increased VEGF-A165b expression in both whole adipose tissue and isolated vascular endothelial cell fractions. This was associated with markedly blunted angiogenic capillary sprout formation in human fat pad explants. Recombinant WNT5A increased secretion of soluble fms-like tyrosine kinase-1 (sFlt-1), a negative regulator of angiogenesis, in the sprout media. Both VEGF-A165b neutralizing antibody and secreted frizzled-related protein 5 (sfrp5), which acts as a decoy receptor for WNT5A, significantly improved capillary sprout formation and reduced sFlt-1 production. We demonstrated a regulatory nexus between WNT5A and VEGF-A165b in the adipose tissue of obese subjects which was linked to angiogenic dysfunction.
- Adipose tissue
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology