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Enhanced Angiogenesis and Reduced Contraction in Thrombospondin-2–null Wounds Is Associated With Increased Levels of Matrix Metalloproteinases-2 and -9, and Soluble VEGF

Susan MacLauchlan¹, Eleni A. Skokos¹, Azin Agah, Jianmin Zeng, Weiming Tian, Jeffrey M. Davidson, Paul Bornstein and Themis R. Kyriakides

Interdepartmental Program in Vascular Biology and Therapeutics and Departments of Pathology and Biomedical Engineering, Yale University, New Haven, Connecticut (SM,EAS,JZ,WT,TRK); Department of Biomedical Sciences, University of South Alabama, Mobile, Alabama (AA); Department of Pathology, Vanderbilt University School of Medicine, and Research Service, Department of Veterans Affairs Medical Center, Nashville, Tennessee (JMD); and Department of Biochemistry and Medicine, University of Washington, Seattle, Washington (PB)

Correspondence to: Themis R. Kyriakides, PhD, Department of Pathology and Biomedical Engineering, Yale University School of Medicine, New Haven, CT 06536-9812. E-mail: themis.kyriakides{at}yale.edu

Thrombospondin-2 (TSP2) is an inhibitor of angiogenesis with pro-apoptotic and anti-proliferative effects on endothelial cells. Mice deficient in this matricellular protein display improved recovery from ischemia and accelerated wound healing associated with alterations in angiogenesis and extracellular matrix remodeling. In this study, we probed the function of TSP2 by performing a detailed analysis of dermal wounds and wound-derived fibroblasts. Specifically, we analyzed incisional wounds by tensiometry and found no differences in strength recovery between wild-type and TSP2-null mice. In addition, analysis of full-thickness excisional wounds by terminal deoxynucleotidyl transferase–mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling stain and MIB-5 immunohistochemistry revealed similar numbers of apoptotic and proliferating cells, respectively. In contrast, the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2, and soluble vascular endothelial growth factor were increased in wounds of TSP2-null mice. Evaluation of the ability of TSP2-null wound fibroblasts to contract collagen gels revealed that it was compromised, even though TSP2-null wounds displayed normal myofibroblast content. Therefore, we conclude that the lack of TSP2 leads to aberrant extracellular matrix remodeling, increased neovascularization, and reduced contraction due in part to elevated levels of MMP-2 and MMP-9. These observations provide in vivo supporting evidence for a newly proposed function of TSP2 as a modulator of extracellular matrix remodeling. (J Histochem Cytochem 57:301–313, 2009)

Key Words: wound healing • angiogenesis • thrombospondin • matrix metalloproteinases • VEGF • wound contraction

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