Enhanced angiogenesis in obesity and in response to PPARgamma activators through adipocyte VEGF and ANGPTL4 production.
PPARgamma activators such as rosiglitazone (RSG) stimulate adipocyte differentiation and increase subcutaneous adipose tissue mass. However, in addition to preadipocyte differentiation, adipose tissue expansion requires neovascularization to support increased adipocyte numbers. Paradoxically, endothelial cell growth and differentiation is potently inhibited by RSG in vitro, raising the question of how this drug can induce an increase in adipose tissue mass while inhibiting angiogenesis. We find that adipose tissue from mice treated with RSG have increased capillary density. To determine whether adipose tissue angiogenesis was stimulated by RSG, we developed a novel assay to study angiogenic sprout formation ex vivo. Angiogenic sprout formation from equally sized adipose tissue fragments, but not from aorta rings, was greatly increased by obesity and by TZD treatment in vivo. To define the mechanism involved in RSG-stimulated angiogenesis in adipose tissue, the expression of proangiogenic factors by adipocytes was examined. Expression of VEGFA and VEGFB, as well as of the angiopoietin-like factor-4 (ANGPTL4), was stimulated by in vivo treatment with RSG. To define the potential role of these factors, we analyzed their effects on endothelial cell growth and differentiation in vitro. We found that ANGPTL4 stimulates endothelial cell growth and tubule formation, albeit more weakly than VEGF. However, ANGPTL4 mitigates the growth inhibitory actions of RSG on endothelial cells in the presence or absence of VEGF. Thus, the interplay between VEGF and ANGPTL4 could lead to a net expansion of the adipose tissue capillary network, required for adipose tissue growth, in response to PPARgamma activators.
Gealekman
Olga
O
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Burkart
Alison
A
Chouinard
My
M
Nicoloro
Sarah M
SM
Straubhaar
Juerg
J
Corvera
Silvia
S
D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015820:Cadherins / Q000032:analysis; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009765:Obesity / Q000503:physiopathology*; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology; D000077205:Pioglitazone; D034741:RNA, Small Interfering / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics; D000099152:Cadherin 5
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D015703:Antigens, CD; D015820:Cadherins; D017077:Culture Media, Conditioned; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D000077205:Pioglitazone; D034741:RNA, Small Interfering; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D000099152:Cadherin 5; C407088:Angptl4 protein, mouse; C467480:vascular endothelial growth factor A, mouse; C467482:vascular endothelial growth factor B, mouse