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High-density lipoprotein (HDL) promotes angiogenesis via S1P3-dependent VEGFR2 activation

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Abstract

High-density lipoprotein (HDL) has previously been shown to promote angiogenesis. However, the mechanisms by which HDL enhances the formation of blood vessels remain to be defined. To address this, the effects of HDL on the proliferation, transwell migration and tube formation of human umbilical vein endothelial cells were investigated. By examining the abundance and phosphorylation (i.e., activation) of the vascular endothelial growth factor receptor VEGFR2 and modulating the activity of the sphingosine-1 phosphate receptors S1P1–3 and VEGFR2, we characterized mechanisms controlling angiogenic responses in response to HDL exposure. Here, we report that HDL dose-dependently increased endothelial proliferation, migration and tube formation. These events were in association with increased VEGFR2 abundance and rapid VEGFR2 phosphorylation at Tyr1054/Tyr1059 and Tyr1175 residues in response to HDL. Blockade of VEGFR2 activation by the VEGFR2 inhibitor SU1498 markedly abrogated the pro-angiogenic capacity of HDL. Moreover, the S1P3 inhibitor suramin prevented VEGFR2 expression and abolished endothelial migration and tube formation, while the S1P1 agonist CYM-5442 and the S1P2 inhibitor JTE-013 had no effect. Last, the role of S1P3 was further confirmed in regulation of S1P-induced endothelial proliferation, migration and tube formation via up-regulation and activation of VEGFR2. Together, these findings argue that HDL promotes angiogenesis via S1P3-dependent up-regulation and activation of VEGFR2 and also suggest that the S1P–S1P3–VEGFR2 signaling cascades as a novel target for HDL-modulating therapy implicated in vascular remodeling and functional recovery in atherosclerotic diseases such as myocardial infarction and ischemic stroke.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Numbers 81471165 and 81670190 to F. Jin, Grant Number 81670189 to Y. Dai); Jilin Provincial Health and Family Planning Research Program (Grant Number 20142041 to F. Jin); German Research Foundation (HE3173/2-1 and HE3173/3-1 to D.M. Hermann); and Dr. Werner-Jackstädt Foundation, and Heinz-Nixdorf Foundation (to F. Jin). We thank Drs. Long Ye (Laboratory of Cancer Precision Medicine) and Yaru Zhang (Department of Neurology) at the First Hospital of Jilin University for their kind assistance with the experiments for revising this paper.

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Authors and Affiliations

  1. Department of Hematology, Cancer Center, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130012, Jilin, China

    Fengyan Jin

  2. Department of Neurology, University Hospital Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Nina Hagemann & Dirk M. Hermann

  3. Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China

    Li Sun & Jiang Wu

  4. Department of Neurology, University of Göttingen Medical School, Göttingen, Germany

    Thorsten R. Doeppner

  5. Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130012, Jilin, China

    Yun Dai

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  1. Fengyan Jin
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  3. Li Sun
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  4. Jiang Wu
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Correspondence to Fengyan Jin, Yun Dai or Dirk M. Hermann.

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Jin, F., Hagemann, N., Sun, L. et al. High-density lipoprotein (HDL) promotes angiogenesis via S1P3-dependent VEGFR2 activation. Angiogenesis 21, 381–394 (2018). https://doi.org/10.1007/s10456-018-9603-z

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