論文

国際誌
2019年6月13日

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

Blood
  • 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
  • Jeffrey A Hubbell
  • 全て表示

133
24
開始ページ
2559
終了ページ
2569
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1182/blood.2019000510

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.

リンク情報
DOI
https://doi.org/10.1182/blood.2019000510
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/30975637
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566593
ID情報
  • DOI : 10.1182/blood.2019000510
  • PubMed ID : 30975637
  • PubMed Central 記事ID : PMC6566593

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