Hypoxia-independent angiogenesis in adipose tissues during cold acclimation.
The molecular mechanisms of angiogenesis in relation to adipose tissue metabolism remain poorly understood. Here, we show that exposure of mice to cold led to activation of angiogenesis in both white and brown adipose tissues. In the inguinal depot, cold exposure resulted in elevated expression levels of brown-fat-associated proteins, including uncoupling protein-1 (UCP1) and PGC-1alpha. Proangiogenic factors such as VEGF were upregulated, and endogenous angiogenesis inhibitors, including thrombospondin, were downregulated. In wild-type mice, the adipose tissues became hypoxic during cold exposure; in UCP1(-/-) mice, hypoxia did not occur, but, remarkably, the augmented angiogenesis was unaltered and was thus hypoxia independent. Intriguingly, VEGFR2 blockage abolished the cold-induced angiogenesis and significantly impaired nonshivering thermogenesis capacity. Unexpectedly, VEGFR1 blockage resulted in the opposite effects: increased adipose vascularity and nonshivering thermogenesis capacity. Our findings have conceptual implications concerning application of angiogenesis modulators for treatment of obesity and metabolic disorders.
Xue
Yuan
Y
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
Petrovic
Natasa
N
Cao
Renhai
R
Larsson
Ola
O
Lim
Sharon
S
Chen
Shaohua
S
Feldmann
Helena M
HM
Liang
Zicai
Z
Zhu
Zhenping
Z
Nedergaard
Jan
J
Cannon
Barbara
B
Cao
Yihai
Y
D000064:Acclimatization; D002001:Adipose Tissue, Brown / Q000033:anatomy & histology / Q000098:blood supply* / Q000378:metabolism; D052436:Adipose Tissue, White / Q000033:anatomy & histology / Q000098:blood supply* / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia; D003080:Cold Temperature; D020869:Gene Expression Profiling; D007473:Ion Channels / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics; D018919:Neovascularization, Physiologic; D000071256:Uncoupling Protein 1; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2