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The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing

Jun Ishihara, Ako Ishihara, Richard D. Starke, Claire R. Peghaire, Koval E. Smith, Thomas A. J. McKinnon, Yoji Tabata, Koichi Sasaki, Michael J. V. White, Kazuto Fukunaga, Mike A. Laffan, Matthias P. Lutolf, Anna M. Randi and Jeffrey A. Hubbell

Key Points

  • VWF heparin-binding domain binds to GFs.

  • VWF heparin-binding domain enhances angiogenesis in wound healing in collaboration with GFs.

Publisher's Note: There is a Blood Commentary on this article in this issue.

Abstract

During wound healing, the distribution, availability, and signaling of growth factors (GFs) are orchestrated by their binding to extracellular matrix components in the wound microenvironment. Extracellular matrix proteins have been shown to modulate angiogenesis and promote wound healing through GF binding. The hemostatic protein von Willebrand factor (VWF) released by endothelial cells (ECs) in plasma and in the subendothelial matrix has been shown to regulate angiogenesis; this function is relevant to patients in whom VWF deficiency or dysfunction is associated with vascular malformations. Here, we show that VWF deficiency in mice causes delayed wound healing accompanied by decreased angiogenesis and decreased amounts of angiogenic GFs in the wound. We show that in vitro VWF binds to several GFs, including vascular endothelial growth factor-A (VEGF-A) isoforms and platelet-derived growth factor-BB (PDGF-BB), mainly through the heparin-binding domain (HBD) within the VWF A1 domain. VWF also binds to VEGF-A and fibroblast growth factor-2 (FGF-2) in human plasma and colocalizes with VEGF-A in ECs. Incorporation of the VWF A1 HBD into fibrin matrices enables sequestration and slow release of incorporated GFs. In vivo, VWF A1 HBD-functionalized fibrin matrices increased angiogenesis and GF retention in VWF-deficient mice. Treatment of chronic skin wounds in diabetic mice with VEGF-A165 and PDGF-BB incorporated within VWF A1 HBD-functionalized fibrin matrices accelerated wound healing, with increased angiogenesis and smooth muscle cell proliferation. Therefore, the VWF A1 HBD can function as a GF reservoir, leading to effective angiogenesis and tissue regeneration.

  • Submitted May 18, 2018.
  • Accepted April 4, 2019.
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