FOXC2 controls Ang-2 expression and modulates angiogenesis, vascular patterning, remodeling, and functions in adipose tissue

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-07, Vol.105 (29), p.10167-10172
• Main Authors: Xue, Yuan, Cao, Renhai, Nilsson, Daniel, Chen, Shaohua, Westergren, Rickard, Hedlund, Eva-Maria, Martijn, Cecile, Rondahl, Lena, Krauli, Per, Walum, Erik, Enerbäck, Sven, Cao, Yihai
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipocytes - metabolism; Adipogenesis - genetics; Adipogenesis - physiology; Adipose Tissue - blood supply; Adipose Tissue - physiology; Adipose Tissue, Brown - blood supply; Adipose Tissue, Brown - physiology; Adipose tissues; Angiogenesis; angiopoietin-2; Angiopoietin-2 - antagonists & inhibitors; Angiopoietin-2 - genetics; Angiopoietin-2 - physiology; Animals; Biological Sciences; Blood vessels; brown adipocytes; Brown adipose tissue; cells; Endothelial cells; endothelial growth-factor; factor gene-expression; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - physiology; Gene expression; Gene Expression Regulation; Genotype & phenotype; in-vitro; leptin; lymphedema-distichiasis syndrome; MEDICIN; Medicin och hälsovetenskap; MEDICINE; messenger-rna expression; Metabolism; Mice; Mice, Transgenic; Neovascularization, Physiologic - genetics; Obesity; Phenotype; Phenotypes; Promoter Regions, Genetic; Renovations; Rodents; Signal Transduction; Social Sciences Interdisciplinary; Tissues; Transgenic animals; Tvärvetenskapliga studier; White adipose tissue
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0802486105

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.