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Angiogenesis

, Volume 22, Issue 1, pp 103–115 | Cite as

Leptin is a physiological regulator of skeletal muscle angiogenesis and is locally produced by PDGFRα and PDGFRβ expressing perivascular cells

  • Emmanuel Nwadozi
  • Andrew Ng
  • Anna Strömberg
  • Hsin-yi Liu
  • Karl Olsson
  • Thomas Gustafsson
  • Tara L. HaasEmail author
Original Paper

Abstract

Skeletal muscle capillarity is characteristically reduced in mature leptin receptor-deficient (Leprdb) mice, which has been attributed to the capillary loss that occurs secondary to metabolic dysfunction. Despite wide recognition of leptin as a pro-angiogenic molecule, the contribution of this adipokine has largely been overlooked in peripheral tissues. Moreover, prior documentation of leptin production within skeletal muscle indicates a potential paracrine role in maintaining local tissue homeostasis. Thus, we hypothesized that leptin is a physiological local paracrine regulator of skeletal muscle angiogenesis and that its production may be modulated by nutrient availability. Leprdb mice exhibited impaired angiogenesis during normal developmental maturation of skeletal myocytes, corresponding with an inability to increase vascular endothelial growth factor-A (VEGFA) mRNA and protein levels between 4 and 13 weeks. In cultured murine and human skeletal myocytes, recombinant leptin increased VEGFA mRNA levels. Leptin mRNA was detectable in skeletal muscle, increasing with prolonged high-fat feeding in mice, and with adiposity in human subjects. Platelet-derived growth factor receptor (PDGFR)α− and PDGFRβ− expressing perivascular cell populations were identified as leptin producing within skeletal muscle of mice and humans. Furthermore, in response to 2 weeks of high-fat feeding, PDGFRβ+ but not PDGFRα+ cells increased leptin production. We conclude that leptin is a physiological regulator of the capillary network in skeletal muscle and stimulates VEGFA production by skeletal myocytes. PDGFRβ expressing perivascular cells exhibit the capacity to act as local “nutrient-sensors” that couple nutrient status to leptin production in skeletal muscle.

Keywords

Leptin Angiogenesis VEGFA Pericyte 

Notes

Acknowledgements

The authors thank Dr. Martina Rudnicki for critical review of the manuscript.

Funding

This study was funded by Canadian Institute of Health Research (CIHR) Grant MOP-107537 (To TLH), Natural Science and Engineering Research Council of Canada grant #222865 (To TLH), Swedish Medical Research Council Grant #2013–09305 (To TG), and the Swedish Research Council for Sport Science (To TG). META-PREDICT study was supported by the European Union Seventh Framework Programme #HEALTH-F2-2012-277936 (To TG). E.N was supported by a doctoral research award from CIHR and an Ontario Graduate Scholarship. KO was supported by a Clinical Scientist Training Programme fellowship from the Karolinska Institutet.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

Animal studies were approved by the York University Committee on Animal Care (#2017-19R3, #2017-20R3) and performed in accordance with the American Physiological Society’s guiding principles in the care and use of animal models. Human studies were approved by the Regional Ethics Review Board in Stockholm (Dnr2006/1232-31/1, 2010/786-31/3, Dnr2012/173-31/3, DNR2012/753-31/2) and performed in accordance with the 1964 Helsinki declaration.

Informed consent

Informed written consent was obtained from all participants following explanation of the experimental procedures.

Supplementary material

10456_2018_9641_MOESM1_ESM.pdf (479 kb)
Supplementary material 1 (PDF 479 KB)

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Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.School of Kinesiology and Health Science and the Muscle Health Research CentreYork UniversityTorontoCanada
  2. 2.Department of Clinical PhysiologyKarolinska University HospitalStockholmSweden
  3. 3.Department of Laboratory Medicine, Clinical PhysiologyKarolinska InstitutetStockholmSweden
  4. 4.Angiogenesis Research Group, Faculty of HealthYork UniversityTorontoCanada

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