Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice.
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 NH(2) terminus of perlecan was removed while the core protein remained intact. Perlecan HS-deficient (Hspg2(Delta3/Delta3)) 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(Delta3/Delta3) mutant mice. Our results suggest that HS in perlecan positively regulates the angiogenesis in vivo.
Zhou
Zhongjun
Z
Department of Biochemistry, Faculty of Medicine, University of Hong Kong, 21 Sassoon Road, Hong Kong, ROC. zhongjun@hkucc.hku.hk
Wang
Jianming
J
Cao
Renhai
R
Morita
Hiroyuki
H
Soininen
Raija
R
Chan
Kui Ming
KM
Liu
Baohua
B
Cao
Yihai
Y
Tryggvason
Karl
K
D000818:Animals; D001485:Basement Membrane / Q000473:pathology; D001808:Blood Vessels / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D003315:Cornea / Q000098:blood supply; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000502:physiology; D019812:Heparan Sulfate Proteoglycans / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D014162:Transfection; D014945:Wound Healing / Q000502:physiology*
D019812:Heparan Sulfate Proteoglycans; D016222:Fibroblast Growth Factor 2; C071927:perlecan