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Impaired Angiogenesis, Delayed Wound Healing and Retarded Tumor Growth in Perlecan Heparan Sulfate-Deficient Mice

¹ Department of Biochemistry, Faculty of Medicine, University of Hong Kong, Hong Kong; ² Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, and ³ Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden; ⁴ Institute of Molecular Medicine, Department of Medicine, University of California at San Diego, La Jolla, California; and ⁵ Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland

Perlecan, a modular proteoglycan carrying primary heparan sulfate (HS) side chains, is a major component of blood vessel basement membranes. It sequesters growth factors such as fibroblast growth factor 2 (FGF-2) and regulates the ligand-receptor interactions on the cell surface, and thus it has been implicated in the control of angiogenesis. Both stimulatory and inhibitory effects of perlecan on FGF-2 signaling have been reported. To understand the in vivo function of HS carried by perlecan, the perlecan gene heparan sulfate proteoglycan 2 (Hspg2) was mutated in mouse by gene targeting. The HS at the NH₂ terminus of perlecan was removed while the core protein remained intact. Perlecan HS-deficient (Hspg2^3/3) mice survived embryonic development and were apparently healthy as adults. However, mutant mice exhibited significantly delayed wound healing, retarded FGF-2-induced tumor growth, and defective angiogenesis. In the mouse corneal angiogenesis model, FGF-2-induced neovascularization was significantly impaired in Hspg2^3/3 mutant mice. Our results suggest that HS in perlecan positively regulates the angiogenesis in vivo.

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