The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing
| Autor: | Michael Laffan, Koval E. Smith, Koichi Sasaki, Jun Ishihara, Matthias P. Lutolf, Jeffrey A. Hubbell, Michael J. V. White, Yoji Tabata, Kazuto Fukunaga, Richard D. Starke, Thomas A. J. McKinnon, Ako Ishihara, Claire Peghaire, Anna M. Randi |
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| Přispěvatelé: | Medical Research Council (MRC), British Heart Foundation |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Platelet-derived growth factor Angiogenesis Immunology Neovascularization Physiologic 030204 cardiovascular system & hematology Biochemistry localization Fibrin Diabetes Mellitus Experimental Extracellular matrix Neovascularization Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein Domains fibronectin hemic and lymphatic diseases von Willebrand Factor medicine Animals Fibroblast 1102 Cardiorespiratory Medicine and Haematology Wound Healing disease Science & Technology model biology Chemistry 1103 Clinical Sciences Cell Biology Hematology Cell biology Fibronectin 030104 developmental biology medicine.anatomical_structure biology.protein 1114 Paediatrics and Reproductive Medicine Intercellular Signaling Peptides and Proteins vwf medicine.symptom Wound healing Life Sciences & Biomedicine a1 domain circulatory and respiratory physiology |
| Zdroj: | Blood. 133:2559-2569 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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