Role of matrix metalloproteinase (MMP)-2 in regulating smooth muscle contraction

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Matrix metalloproteinases (MMPs) are proteins known to cause structural and functional changes in blood vessels by cutting other proteins into smaller pieces. MMP-2 is found in vascular smooth muscle and endothelial cells and has been studied for its important role in the regulation of vascular contraction. MMPs are produced without any activity and they need other proteins or oxidative stress to activate them. The Schulz lab was the first to show that MMP-2 is activated within cardiac cells by oxidative stress. Once activated, MMP-2 destroys proteins such as troponin and titin which are essential for normal heart muscle contraction. Thus we thought to test if there are similarly targeted contractile proteins in blood vessels which are susceptible to destruction by MMP-2 and if this affects the contraction of blood vessels. Calponin, smoothelin-B and smitin are contractile proteins found in smooth muscle cells which are structurally similar to troponin and titin. They help to maintain constriction and keep blood pressure normal. As troponin and titin are destroyed by MMP-2 in cardiac cells, calponin, smoothelin-B and smitin may be targets of MMP-2 in smooth muscle cells which may result in poor contractile function and low blood pressure. We showed that MMP-2 is activated in rat blood vessels during oxidative stress induced by bacterial toxins and that MMP inhibitor drugs improved vascular contraction in these rats. This led our lab to test if MMP-2 cleaves contractile proteins in vascular smooth muscle and contributes to the loss of contractile function. We wish to test in this proposal an exciting and novel concept that activated MMP-2 may destroy key proteins that control normal vascular smooth muscle contraction. This important idea may help us in the understanding of mechanisms involved in controlling blood pressure and new pharmacological approaches to regulate it.