Regulation of Vascular Smooth Muscle Cell Migration and Proliferation In Vitro and in Injured Rat Arteries by a Synthetic Matrix Metalloproteinase Inhibitor

Abstract

Smooth muscle cell (SMC) migration and proliferation and extracellular matrix remodeling are essential aspects of the arterial response to injury, vessel development, and atherogenesis. Matrix metalloproteinase (MMP) expression is associated with SMC proliferation and migration after arterial injury. To assess the role of MMPs in SMC proliferation and migration and intimal thickening, we measured the effect of the synthetic MMP inhibitor BB94 (Batimastat) on DNA synthesis and migration of SMCs in vitro as well as the formation of a neointima after balloon injury to the rat carotid artery. BB94 dose-dependently inhibited SMC migration induced by platelet-derived growth factor (PDGF)-BB through a filter coated with a thick basement membrane matrix (Matrigel) layer but did not show any inhibitory effect on SMC migration through a lightly coated filter. At concentrations up to 1 mumol/L, BB94 did not alter DNA synthesis induced by PDGF-AA or PDGF-BB. Treatment with 30 mg BB94.kg-1.d-1 IP for 7 or 14 days after balloon injury to the rat carotid artery decreased the total number of intimal SMC nuclei and suppressed intimal thickening. SMC proliferation (5-bromo-2'-deoxyuridine labeling) was decreased in the media at 2 days, whereas it was increased in the intima at 7 but not 14 days. These results suggest that BB94 inhibits intimal thickening after arterial injury by decreasing SMC migration and proliferation and support the conclusion that MMPs play a significant role in regulating intimal thickening in injured arteries.

HMG-CoA Reductase Inhibitors Reduce MMP-9 Secretion by Macrophages

“…33 The synthetic MMP inhibitor BB94 (Batimastat) inhibits gelatinases A and B with IC 50 values of 4 and 10 nmol/L, respectively, 34 and is able to reduce intimal thickening after arterial injury by decreasing both SMC migration and proliferation. 35 These data support the conclusion that MMPs play a significant role in regulating intimal thickening in injured arteries and therefore in atherogenesis.…”

Effects of heparin on the production of homocysteine-induced extracellular matrix metalloproteinase-2 in cultured rat vascular smooth muscle cells

“…Only MMP-2 and gelatinase B are expressed as latent proenzymes by aortic SMCs, and both are involved in arterial diseases, such as atherosclerosis and abdominal aortic aneurysms. It has been reported that the migration and proliferation of VSMCs, which contribute to the morphogenesis of atherosclerotic plaques, require the ECM remodelling caused by MMPs (2). The production of MMPs in VSMCs is known to be regulated by a number of cytokines and growth factors, such as platelet-derived growth factor secreted by platelets and vascular cells (1,11,18).…”

“…These events are known to be regulated by various cytokines and growth factors secreted by platelets and vascular cells (1). Zempo et al (2) reported that the processes of migration and proliferation of VSMCs that contribute to the morphogenesis of atherosclerotic plaque require ECM remodelling caused by matrix metalloproteinases (MMPs). Brown et al (3) identified MMPs in human coronary atherosclerotic lesions and suggested that MMPs are closely related to the progression of atherosclerosis.…”

Smoking, Metalloproteinases, and Vascular Disease

“…40 Matrix metalloproteinase activity is correlated with VSMC migration and proliferation after vascular injury, [41][42][43] and inhibition of matrix metalloproteinase activity suppresses VSMC proliferation. 41,44,45 Furthermore, matrix metalloproteinase expression is associated with remodeling of the vascular adventitia. 42,46 Characteristics of unstable plaques susceptible to rupture include a large lipid core, a thin fibrous cap, 47 and intraplaque hemorrhage.…”