Stromal cell-derived factor 1 (SDF1) attenuates platelet-derived growth factor-B (PDGF-B)-induced vascular remodeling fo
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ORIGINAL PAPER
Stromal cell‑derived factor 1 (SDF1) attenuates platelet‑derived growth factor‑B (PDGF‑B)‑induced vascular remodeling for adipose tissue expansion in obesity Eri Watanabe1 · Tsutomu Wada1 · Akira Okekawa1 · Fuka Kitamura1 · Go Komatsu1 · Yasuhiro Onogi1 · Seiji Yamamoto2 · Masakiyo Sasahara2 · Munehiro Kitada3 · Daisuke Koya3 · Hiroshi Tsuneki1 · Toshiyasu Sasaoka1 Received: 14 April 2020 / Accepted: 10 July 2020 © Springer Nature B.V. 2020
Abstract Platelet-derived growth factor-B (PDGF-B) is a main factor to promote adipose tissue angiogenesis, which is responsible for the tissue expansion in obesity. In this process, PDGF-B induces the dissociation of pericytes from blood vessels; however, its regulatory mechanism remains unclear. In the present study, we found that stromal cell-derived factor 1 (SDF1) plays an essential role in this regulatory mechanism. SDF1 mRNA was increased in epididymal white adipose tissue (eWAT) of obese mice. Ex vivo pharmacological analyses using cultured adipose tissue demonstrated that physiological concentrations (1–100 pg/mL) of SDF1 inhibited the PDGF-B-induced pericyte dissociation from vessels via two cognate SDF1 receptors, CXCR4 and CXCR7. In contrast, higher concentrations (> 1 ng/mL) of SDF1 alone caused the dissociation of pericytes via CXCR4, and this effect disappeared in the cultured tissues from PDGF receptor β (PDGFRβ) knockout mice. To investigate the role of SDF1 in angiogenesis in vivo, the effects of anagliptin, an inhibitor of dipeptidyl peptidase 4 (DPP4) that degrades SDF1, were examined in mice fed a high-fat diet. Anagliptin increased the SDF1 levels in the serum and eWAT. These changes were associated with a reduction of pericyte dissociation and fat accumulation in eWAT. AMD3100, a CXCR4 antagonist, cancelled these anagliptin effects. In flow-cytometry analysis, anagliptin increased and decreased the PDGF-B expression in endothelial cells and macrophages, respectively, whereas anagliptin reduced the PDGFRβ expression in pericytes of eWAT. These results suggest that SDF1 negatively regulates the adipose tissue angiogenesis in obesity by altering the reactivity of pericytes to PDGF-B. Keywords Anagliptin · Angiogenesis · DPP4 inhibitor · Obesity · Pericytes
Eri Watanabe and Tsutomu Wada have contributed equally to this article. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09738-6) contains supplementary material, which is available to authorized users. * Tsutomu Wada [email protected]‑toyama.ac.jp * Toshiyasu Sasaoka [email protected]‑toyama.ac.jp 1
Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama 930‑0194, Japan
2
Department of Pathology, University of Toyama, 2630 Sugitani, Toyama 930‑0194, Japan
3
Department of Diabetology and Endocrinology, Kanazawa Medical University, 1‑1 Daigaku, Uchinada, Ishikawa 920‑0293, Japan
Introduction The accumulation of abdominal fat and excessive expansion of adipose tissues are closely associated with the
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