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ADAMTS13 and its variants promote angiogenesis via upregulation of VEGF and VEGFR2

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Abstract

Severe plasma ADAMTS13 deficiency results in the clinical disorder thrombotic thrombocytopenic purpura. However, other potential pathophysiological roles of ADAMTS13 in endothelial cell biology remain unexplored. The goals of this study were to understand the angiogenic pathways ADAMTS13 activates and to identify the important structural components of ADAMTS13 that stimulate angiogenesis. Incubation of human umbilical vein endothelial cells (HUVEC) with 150 ng/mL (1 nM) of recombinant human ADAMTS13 induced VEGF expression by 53 % and increased VEGF mRNA by over sixfold, both within 10 min; the measured VEGF levels steadily decreased over 2 h, as shown by Western blot and ELISA. Phosphorylation of VEGFR2 was significantly enhanced in HUVEC after incubation with ADAMTS13 (1 nM). Structure–function analysis showed that an ADAMTS13 variant containing thrombospondin type 1 (TSP1) 2–8 repeats (TSP1 2–8), TSP1 2–8 plus CUB domains (TSP1 2–8 plus CUB), or TSP1 5–8 repeats plus CUB domains (TSP1 5–8 plus CUB) increased HUVEC proliferation by 41–54 % as compared to the EBM-2 controls. Chemotaxis assays further demonstrated that the TSP1 domains of ADAMTS13 increased HUVEC migration by 2.65-fold. Incubation of HUVEC with both ADAMTS13 variants containing TSP1 repeats and anti-VEGF IgG abrogated the enhanced effect of ADAMTS13 on proliferation, migration, and VEGFR2 phosphorylation. In conclusion, ADAMTS13-induced endothelial cell angiogenesis occurs via the upregulation of VEGF and phosphorylation of VEGFR2. This angiogenic activity depends on the C-terminal TSP1 repeats of ADAMTS13.

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Acknowledgments

We thank Mr. Jonathan Baza and Miss Courtney Hoyt for their help in culturing HUVEC. This study is partially supported by grants from American Heart Association-EIA 0940100 N, National Institutes of Health HL074124-Project 3 and National Institutes of Health HL115187001A1 to X.L.Z., and by the ARUP Laboratories Institute for Research and Development to G.R. The authors do not have any conflicts of interests to disclose.

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Authors and Affiliations

  1. Division of Hematology and Hematologic Malignancies, University of Utah Health Sciences Center, 30 N 1900 E Room 5C402, Salt Lake City, UT, 84132, USA

    Manfai Lee, Justin Keener & George M. Rodgers

  2. Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, PA, 19104, USA

    Juan **ao & X. Long Zheng

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  1. Manfai Lee
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  2. Justin Keener
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  3. Juan **ao
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  4. X. Long Zheng
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  5. George M. Rodgers
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Correspondence to Manfai Lee.

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Lee, M., Keener, J., **ao, J. et al. ADAMTS13 and its variants promote angiogenesis via upregulation of VEGF and VEGFR2. Cell. Mol. Life Sci. 72, 349–356 (2015). https://doi.org/10.1007/s00018-014-1667-3

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  • DOI: https://doi.org/10.1007/s00018-014-1667-3

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