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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 AJ McKinnon, Yoji Tabata, Koichi Sasaki, Michael JV White, Kazuto Fukunaga, Michael A Laffan, Matthias P Lutolf, Anna M Randi and Jeffrey A Hubbell

Key Points

  • VWF heparin binding domain binds to growth factors.

  • VWF heparin binding domain enhances angiogenesis in wound healing in collaboration with growth factors.

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 GFs 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 where 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 (VEGF)-A isoforms and platelet derived growth factor (PDGF)-BB, mainly through the heparin-binding domain (HBD) within the VWF A1 domain. VWF also binds to VEGF-A and FGF-2 in human plasma and co-localizes with VEGF-A in EC. 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 GFs reservoir, leading to effective angiogenesis and tissue regeneration.

  • Submitted March 8, 2019.
  • Revision received April 5, 2019.
  • Accepted April 4, 2019.