Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 14; pp. 4699 - 4702
• Main Authors: ZHONGJUN ZHOU, JIANMING WANG, RENHAI CAO, MORITA, Hiroyuki, SOININEN, Raija, KUI MING CHAN, LIU, Baohua, CAO, Yihai, TRYGGVASON, Karl
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.2004
• Subjects: Animals; Antineoplastic agents; Basement Membrane - pathology; Biological and medical sciences; Blood Vessels - pathology; Cell Division - physiology; Cornea - blood supply; Female; Fibroblast Growth Factor 2 - genetics; Fibroblast Growth Factor 2 - physiology; Heparan Sulfate Proteoglycans - deficiency; Heparan Sulfate Proteoglycans - genetics; Male; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - genetics; Neoplasms, Experimental - pathology; Neovascularization, Pathologic - pathology; Neovascularization, Physiologic - physiology; NIH 3T3 Cells; Pharmacology. Drug treatments; Transfection; Tumors; Wound Healing - physiology; Angiogenesis; Vertebrata; Mammalia; Mouse; Tumor growth; Animal; Rodentia; Heparitin sulfate; Neovascularization; Malignant tumor; Cicatrization
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-0810

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.