The SDF1-CXCR4 Signals Regulate Adipose Tissue Expansion by Modulating Angiogenesis in Diet-Induced Obesity in Mice

Abstract

Adipose tissue (AT) expands with angiogenesis in obesity. Mature vessels in the epididymal white adipose tissue (eWAT) are tightly wrapped with pericytes (PCs), which attenuates endothelial (ECs) proliferation. We found that obesity-associated increase of PDGF-B promoted detachment of PCs from nature vessels; thereby vessels were prone to neoangiogenesis. In this study, we aimed to clarify the role of stromal cell derived factor 1 (SDF1), another proangiogenic factor in the AT development in obesity. In the whole-mount immunofluorescence study of organ cultured eWAT, treatment with PDGF-B or SDF1 for 24 h significantly promoted detachment of PCs from vessels. The effect of SDF1 on PCs was reproduced by treatment with ATI2341, a potent CXCR4 agonist, but not by VUX11207, a CXCR7 agonist. Interestingly, PCs were well associated with vessels when tissue was treated with both PDGF-B and SDF1. In addition, the association was declined by preincubation with AMD3100, a CXCR4 antagonist or when AT was derived from Pdgfrb knockout mice. To further explore the in vivo effect of SDF1 in AT during obesity, we administrated Anagliptin (Ana), a DPP-4 inhibitor to C57BL/6J mice fed chow or HFD for 12 weeks, since SDF1 is a known substrate for DPP-4. The protein amount of SDF1 was significantly elevated in the eWAT of Ana-treated mice. Importantly, HFD-induced adipose tissue expansion was significantly attenuated with reduced vascular density and PCs detachment in the eWAT by Ana. To clarify the mechanism by which PCs attach even under HFD-fed condition by coexistence of SDF1 and PDGF-B, we isolated ECs, PCs, and macrophages (Mφ) from eWAT of mice. Expression of PDGFB was increased in Mφ and decreased in ECs by HFD, whereas these changes were attenuated and the gradient of PDGFB concentration between PCs and ECs was blunted in Ana-treated eWAT. These findings suggest that both PDGF-B and SDF1 coordinately regulate PCs detachments and adipose tissue expansion with obesity in mice. Disclosure T. Wada: Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. E. Watanabe: None. Y. Kotera: None. Y. Onogi: None. H. Tsuneki: None. T. Sasaoka: None.