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Stromal cell-derived factor 1 (SDF1) attenuates platelet-derived growth factor-B (PDGF-B)-induced vascular remodeling for adipose tissue expansion in obesity

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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.

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Acknowledgements

This study was supported by JSPS KAKENHI Grant Number JP24591318 (to T.W.), a research grant from the Sanwa Kagaku Kenkyusho (to T.S. and T.W.), and a research grant from Novartis Pharma Corporation (to T.W.). The authors thank Y. Kurashige and T. Matsushima at the Department of Pathology, and Y. Kotera and Y. Miyazawa at the Department of Clinical Pharmacology, University of Toyama, for their excellent technical assistance.

Funding

This study was supported by JSPS KAKENHI grant number 18K08469 (to T.W.), a research Grant from the Sanwa Kagaku Kenkyusho (to T.S. and T.W.), and a research grant from Novartis Pharma Corporation (to T.W.).

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  1. Eri Watanabe and Tsutomu Wada have contributed equally to this article.

Authors and Affiliations

  1. Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Eri Watanabe, Tsutomu Wada, Akira Okekawa, Fuka Kitamura, Go Komatsu, Yasuhiro Onogi, Hiroshi Tsuneki & Toshiyasu Sasaoka

  2. Department of Pathology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan

    Seiji Yamamoto & Masakiyo Sasahara

  3. Department of Diabetology and Endocrinology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan

    Munehiro Kitada & Daisuke Koya

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  1. Eri Watanabe
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Contributions

Conceptualization: TW; Methodology: TW, EW, and YO; Formal analysis and investigation: TW, EW, AO, FK, GK, and YO; Writing—original draft preparation: TW; Writing—review and editing: TW, EW, HT, and TS; Funding acquisition: TW, TS; Supervision: TW, and TS. All the authors shared ideas and contributed to the discussion, and commented on the manuscript.

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Correspondence to Tsutomu Wada or Toshiyasu Sasaoka.

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Watanabe, E., Wada, T., Okekawa, A. et al. Stromal cell-derived factor 1 (SDF1) attenuates platelet-derived growth factor-B (PDGF-B)-induced vascular remodeling for adipose tissue expansion in obesity. Angiogenesis 23, 667–684 (2020). https://doi.org/10.1007/s10456-020-09738-6

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