title: Hypoxia-independent angiogenesis in adipose tissues during cold acclimation.
abstract: 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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xue
authors.forename: Natasa
authors.initials: N
authors.lastname: Petrovic
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.forename: Ola
authors.initials: O
authors.lastname: Larsson
authors.forename: Sharon
authors.initials: S
authors.lastname: Lim
authors.forename: Shaohua
authors.initials: S
authors.lastname: Chen
authors.forename: Helena M
authors.initials: HM
authors.lastname: Feldmann
authors.forename: Zicai
authors.initials: Z
authors.lastname: Liang
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Jan
authors.initials: J
authors.lastname: Nedergaard
authors.forename: Barbara
authors.initials: B
authors.lastname: Cannon
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: 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
chemical_list: 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