Removal of heparan sulfate by heparinase treatment inhibits FGF-2-dependent smooth muscle cell proliferation in injured rat carotid arteries

• Published in: Atherosclerosis 2004-07, Vol.175 (1), p.51-57
• Main Authors: Kinsella, Michael G, Irvin, Colleen, Reidy, Michael A, Wight, Thomas N
• Format: Article
• Language: English
• Subjects: Animals; Arterial injury; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Bromodeoxyuridine - metabolism; Cardiology. Vascular system; Carotid Arteries - metabolism; Carotid Arteries - pathology; Carotid Artery Injuries - metabolism; Carotid Artery Injuries - pathology; Catheterization; Cell Division - drug effects; Cell proliferation; Chondroitin ABC Lyase - pharmacology; Endothelium, Vascular - injuries; Endothelium, Vascular - pathology; Fibroblast Growth Factor 2 - pharmacology; Fibroblast Growth Factor 2 - physiology; Fibroblast growth factor-2; Fundamental and applied biological sciences. Psychology; Heparan sulfate; Heparan Sulfate Proteoglycans - metabolism; Heparin Lyase - pharmacology; Heparinase; Heparitin Sulfate - metabolism; Immunohistochemistry; In Vitro Techniques; Medical sciences; Muscle, Smooth, Vascular - injuries; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Neurosurgery; Rats; Rats, Sprague-Dawley; Skull, brain, vascular surgery; Smooth muscle; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Vertebrates: cardiovascular system
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2004.01.045

Smooth muscle cells (SMC) of the rat carotid arterial media proliferate and migrate in response to injury during the formation of a neointima. The interaction of fibroblast growth factor (FGF-2), which is released at the site of injury, with heparan sulfate proteoglycans (HSPGs) is necessary to induce signaling, which elicits an FGF-dependent mitogenic response by arterial smooth muscle cells, and also serves as a mechanism for storage of the growth factor within the extracellular matrix. However, whether these interactions are critical during neointimal formation has not been directly tested. In this study, a model of FGF-2-dependent medial SMC mitogenic response in balloon-injured rat carotid artery was used to test the effect of degradation of vessel wall heparan sulfate on subsequent SMC proliferation. Treatment of balloon-catheterized rat carotid arteries with chondroitin ABC lyase and/or heparin lyases eliminated heparan sulfates in the vessel wall, as determined by immunoperoxidase staining. In contrast, the distribution in the carotid vessel wall of the large core protein of perlecan, a major vessel wall HSPG that binds FGF-2, is not decreased. The effect of glycosaminoglycan digestion in situ on medial SMC proliferation in response to a bolus injection of FGF-2 after injury was determined by measuring the percentage of SMC nuclei that incorporated 5-bromo-2′-deoxyuridine (BrdU) 48 h after injury. Enzymatic removal of heparan sulfate reduced BrdU incorporation into medial SMC by 60–70% ( P