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.

Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature

“…Consistent with these genetic findings, VEGFR1 blockade could further facilitate neovascularization. For example, inhibition of VEGFR1 in adipose tissues results in accelerated angiogenesis rather than suppression of neovascularization (51). These findings show the primary function of VEGFR1 as a negative modulator of angiogenesis.…”

“…In subsets of experiments, tumor-bearing mice were randomly divided into different groups (n ϭ 6 -8 per group) and received treatment with VEGFR1, VEGFR2 or VEGFR1/VEGFR2 blockades as previous described (49,51). The treatment started at day 0 after tumor implantation and administration of anti-VEGFR1 (MF1, Imclone Inc., 600 g/mouse) or anti-VEGFR2 (DC101, Imclone Inc., 600 g/mouse) twice a week for a total of 2-week therapy.…”

Brown and beige fat: development, function and therapeutic potential

“…In addition, cold exposure induces the sprouting and growth of blood vessels in adipose to facilitate oxygen delivery and heat exchange 70,72,88 . This angiogenic effect is regulated through increased production of vascular endothelial growth factor (Vegf) by a mechanism that does not involve hypoxia [89][90][91] . Interestingly, Vegf secreted by adipose tissue also enhances the recruitment of brown and beige adipocytes through an unknown mechanism (Fig.…”

Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis

“…Immunohistochemical staining of whole-mount tissue samples was performed according to our previously published methods [33][34][35][36][37][38] . Treated and non-treated tumour tissues were fixed with 4% PFA overnight and cut into small pieces.…”