This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of our research is to understand how vascularization of atherosclerotic lesions contributes to plaque destabilization and rupture. Plaque vascularization and intraplaque hemorrhage have been correlated with plaque rupture in human artery specimens. Previous studies have demonstrated that matrix metalloproteinase(MMP)-9 is important for capillary branching during angiogenesis induced by tissue ischemia. In this study, we will specifically examine the role of MMP-9 in the vascularization of atherosclerotic plaques by comparing angiogenesis in carotid artery lesions of apolipoprotein E (apoE) knockout and apoE MMP-9 double knockout mice. Lesions will be induced using the carotid ligation method. Plaque angiogenesis will be quantified in frozen sections of ligated carotid arteries 14 and 21 days after lesion induction using immunohistochemistry for CD31, von Willebrand factor, and smooth muscle ?-actin. We will measure functional perfusion capacity of the plaque microvasculature by perfusing the vessels with fluorescent microspheres followed by xylene extraction. We will also reconstruct the three-dimensional structure of the microvasculature within carotid artery lesions using fluorescence microangiography and confocal microscopy, in order to measure the number of capillary branch points. We expect to observe defects in both functional perfusion capacity and in capillary branching in MMP-9-deficient animals. We also hope to extend this work to examine transcapillary permeability of angiogenic microvessels within lesions in the two mouse strains, to determine whether MMP-dependent degradation of endothelial basement membranes during angiogenesis can alter macromolecular transport within the plaque.
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