(Verbatim from the application): Vascular remodeling represents an adaptation to hemodynamic conditions and repair after injury. Pathological arterial remodeling narrows the arterial lumen, compromising tissue perfusion, and is therefore an important target for therapeutic intervention. In vitro, matrix metalloproteinase-9 (MMP-9) degrades the major arterial matrix components, collagen and elastin, and facilitates smooth muscle cell (SMC) migration and proliferation. Based on this type of observations, MMP-9 has been assumed to be essential for vascular remodeling. We plan to directly examine the role of MMP-9 in vivo by studying MMP-9-deficient mice. We will examine remodeling of mouse carotid arteries triggered by flow cessation, a model selected based on robust induction of intimal hvperplasia and lumen narrowing. In preliminary experiments, we found a dramatic difference between the morphology of both the ligated and contralateral carotid arteries of wild-type WT and MMP-9 deficient (KO) mice. While MMP-9 deficiency inhibited intimal hyperplasia of ligated artery, it increased cell numbers in the media and adventitia, suggesting cell entrapment due to impaired migration. In addition, greatly enhanced collagen and elastin accumulation was detected in MMP-9 KO mice, especially in the adventitia, likely resulting in arterial constriction. We therefore hypothesize that MMP-9 is necessary for repair and for positive vascular remodeling. We will pursue the following Aims: 1) Test in vivo the role of MMP-9 in the formation of intimal hyperplasia and positive arterial remodeling. Identify other components of arterial remodeling requiring the action of MMP-9; 2) Determine the contribution of MMP9 to vascular SMC migration and proliferation; processes essential for the development of intimal hyperplasia; 3) Assess MMP-9 participation in the control of vascular matrix metabolism during carotid artery remodeling induced by vascular injury; and 4) Assess the role of MMP-9 in angiogenesis of vasa vasorum. Beyond our basic interest in MMP-9, we believe our model provides an opportunity to examine the contribution of the arterial matrix to pathological remodeling in general. These studies will identify components of arterial remodeling that are dependent on the action of MMP-9, which should help clarify its suitability as a therapeutic target in restenosis.
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