Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity

Abstract

The biological role of macrophage infiltration into adipose tissue in obesity remains to be fully understood. We hypothesize that macrophages may act to stimulate angiogenesis in the adipose tissue. This possibility was examined by determining macrophage expression of angiogenic factor PDGF (platelet-derived growth factor) and regulation of tube formation of endothelial cells by PDGF. The data suggest that endothelial cell density was reduced in the adipose tissue of ob/ob mice. Expression of endothelial marker CD31 was decreased in protein and mRNA. The reduction was associated with an increase in macrophage infiltration. In the obese mice, PDGF concentration was elevated in the plasma, and its mRNA expression was increased in adipose tissue. Macrophages were found to be a major source of PDGF in adipose tissue, as deletion of macrophages led to a significant reduction in PDGF mRNA. In cell culture, PDGF expression was induced by hypoxia, and tube formation of endothelial cells was induced by PDGF. The PDGF activity was dependent on S6K, as inhibition of S6K in endothelial cells led to inhibition of the PDGF activity. We conclude that, in response to the reduced vascular density, macrophages may express PDGF in adipose tissue to facilitate capillary formation in obesity. Although the PDGF level is elevated in adipose tissue, its activity in angiogenesis is dependent on the availability of sufficient endothelial cells. The study suggests a new function of macrophages in the adipose tissue in obesity.

Adipose Tissue-specific Inhibition of Hypoxia-inducible Factor 1α Induces Obesity and Glucose Intolerance by Impeding Energy Expenditure in Mice*

“…As a major hypoxia-responsive gene, the protein abundance of HIF1␣ and its transcriptional activity in adipose tissue are elevated in obese adipose tissue (7,11,26). It has been postulated that local hypoxia instigates macrophage infiltration and inflammation in obese adipose tissue through activation of HIF1␣ (34). Indeed, a recent report from Scherer and colleagues (26) demonstrates that transgenic expression of a constitutively active form of HIF1␣ induces fibrosis and inflammation in WAT, leading to impaired glucose tolerance in mice.…”

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

“…1,2,38 We postulated, therefore, that 14S,21R-diHDHA enhances the functions of db/db macrophages in angiogenesis, in part, by increasing their angiogenic cytokine production. The results demonstrated that lesser amounts of VEGF and PDGF-BB were released by db/db macrophages than by db/ϩ macrophages ( Figure 3, E and F), consistent with impaired functions of db/db macrophages.…”

Macrophages and CSF-1

“…35,36 Another developmental function of macrophages is the provision of trophic support. As potent effector cells, macrophages produce a range of mediators including plateletderived growth factors (PDGFs), 37 transforming growth factors (TGFs), 38 insulin-like growth factor (IGF)-1 39 and Wnts. [40][41][42] Macrophage-derived factors mediate cell fate decisions, as observed in β cell differentiation in the developing pancreas 43 and hepatic progenitor differentiation during liver regeneration.…”

“…40 Macrophages also contribute to development through angiogenic regulation. 30 In addition to the production of a range of pro-and anti-angiogenic factors, 36,37,42 macrophages have been shown to assist in vascular patterning by physically directing angiogenic positioning.…”