Antiangiogenic actions of vascular endothelial growth factor-A165b, an inhibitory isoform of vascular endothelial growth factor-A, in human obesity

Bates, David; Ngo, Doan T. M.; Farb, Melissa G.; Kikuchi, Ryosuke; Karki, Shakun; Tiwari, Stephanie; Bigornia, Sherman J.; LaValley, Michael P.; Hamburg, Naomi M.; Vita, Joseph A.; Hess, Donald T.; Walsh, Kenneth; Gokce, Noyan

Abstract

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 antiangiogenic 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 (body mass index, 45±8 kg/m2 ; age, 45±11 years) 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 with subcutaneous fat (P less than 0.001) that was associated with marked tissue upregulation of VEGF-A165b (P=0.004). The extent of VEGF-A165b expression correlated negatively with angiogenic growth (r=−0.6, P=0.006). Although 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 with lean control subjects (P=0.02), and surgical weight loss induced a marked decline in serum VEGF-A165b (P=0.003).
Conclusions—We demonstrate that impaired adipose tissue angiogenesis is associated with overexpression of a novel antiangiogenic factor, VEGF-A165b, that may play a pathogenic role in human adiposopathy. Moreover, systemic upregulation 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 the cardiometabolic consequences of obesity .

• Journal Article Type: Article
• Acceptance Date: Jul 3, 2014
• Publication Date: Aug 15, 2014
• Deposit Date: Jul 10, 2018
• Print ISSN: 0009-7322
• Electronic ISSN: 1524-4539
• Publisher: American Heart Association
• Peer Reviewed: Peer Reviewed
• Volume: 130
• Issue: 13
• Pages: 1072-1080
• DOI: https://doi.org/10.1161/CIRCULATIONAHA.113.008171
• Public URL: https://nottingham-repository.worktribe.com/output/1114839
• Publisher URL: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.113.008171
• PMID: 25116954