FOXC2 controls Ang-2 expression and modulates angiogenesis, vascular patterning, remodeling, and functions in adipose tissue.
Adipogenesis is spatiotemporally coupled to angiogenesis throughout adult life, and the interplay between these two processes is communicated by multiple factors. Here we show that in a transgenic mouse model, increased expression of forkhead box C2 (FOXC2) in the adipose tissue affects angiogenesis, vascular patterning, and functions. White and brown adipose tissues contain a considerably high density of microvessels appearing as vascular plexuses, which show redistribution of vascular smooth muscle cells and pericytes. Dysfunction of these primitive vessels is reflected by impairment of skin wound healing. We further provide a mechanistic insight of the vascular phenotype by showing that FOXC2 controls Ang-2 expression by direct activation of its promoter in adipocytes. Remarkably, an Ang-2-specific antagonist almost completely reverses this vascular phenotype. Thus, the FOXC2-Ang-2 signaling system is crucial for controlling adipose vascular function, which is part of an adaptation to increased adipose tissue metabolism.
Xue
Yuan
Y
Department of Microbiology, Laboratory of Angiogenesis Research, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
Cao
Renhai
R
Nilsson
Daniel
D
Chen
Shaohua
S
Westergren
Rickard
R
Hedlund
Eva-Maria
EM
Martijn
Cecile
C
Rondahl
Lena
L
Krauli
Per
P
Walum
Erik
E
Enerbäck
Sven
S
Cao
Yihai
Y
D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D000273:Adipose Tissue / Q000098:blood supply* / Q000502:physiology*; D002001:Adipose Tissue, Brown / Q000098:blood supply / Q000502:physiology; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D000818:Animals; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic; D015398:Signal Transduction
D042702:Angiopoietin-2; D051858:Forkhead Transcription Factors; C082078:mesenchyme fork head 1 protein