Heparan-Sulfate Deficient Perlecan Mice Exhibit Increased Vascular Smooth Muscle Cell Activity And Response To Arterial Injury
Circulation(2008)
Abstract
Percutaneous coronary interventions (PCI) are limited by restenosis, a process that involves smooth muscle cell (SMC) proliferation and migration. Perlecan, a heparan-sulfate proteoglycan present in the vessel wall has been shown to inhibit SMC activity in vitro, and decrease intimal hyperplasia in animal models of arterial injury. As well, heparinase treatment of perlecan results in a loss of these inhibitory effects in vitro. This study examined the hypothesis that heparan sulfate (HS) has an inhibitory role in perlecan’s regulation of SMC activity. Aortic SMC from transgenic mice expressing HS-deficient Perlecan (M Δ3/Δ3 ) and control (WT) mice were isolated and cultured to characterize SMC activity. Additionally, M Δ3/Δ3 and control mice underwent a carotid artery wire injury and carotid arteries were harvested 1 week (n=6) and 3 weeks (n=12) post-surgery for histological analysis. Over 7 days, M Δ3/Δ3 cells showed significantly higher proliferation during the log phase (days 2–4), with almost a 2-fold increase in cell density during the plateau phase (days 5–7), compared to WT SMC (p<0.001). Incubation with FGF-2 or PDGF-BB resulted in significantly greater M Δ3/Δ3 cell density versus WT (p<0.001). PDGF-BB induced migration was also significantly greater in the M Δ3/Δ3 cells (216.2 ± 2.81) than the WT cells (151.9 ± 2.97) (p<0.01). Following arterial injury, significant medial thickening was seen at 1 and 3 weeks, in WT and M Δ3/Δ3 arteries. Increases in medial thickness of M Δ3/Δ3 arteries were significantly greater than those seen in WT arteries at all respective time points (p<0.001). In conclusion, the differences seen in SMC activity and response to arterial injury between WT and M Δ3/Δ3 populations demonstrate that the HS side chains play a critical role in perlecan’s inhibitory effects of SMC activity, and may indicate a promising therapeutic target for the prevention of restenosis following PCI.
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Key words
Pericytes
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