: Obstructive vascular diseases (OVD) are the dominant cause of mortality in the developed nations. The dedifferentiation of vascular smooth muscle cells (vsmcs) and their subsequent proliferation and luminal accumulation following vascular injury are pathologic hallmarks of these diseases. In the absence of disease, the mature artery is composed of alternating rings of elastic fibers and vsmcs that surround the endothelium. Elastic fibers are an extensively cross-linked network of the matrix protein elastin. Our previous work demonstrated that mutations in the elastin gene are responsible for a human vascular disease, and loss of elastin is sufficient for inducing an obstructive vascular pathology in mice. We hypothesize that disruption of the elastin matrix is central to the pathogenesis of OVD. We propose three aims.
Aim 1 : We will compare the differentiation, migration and proliferation of vsmcs isolated from mice lacking elastin (Eln -/-) with wild type controls. Our preliminary data indicated that elastin stimulates vsmcs to differentiate into a contractile phenotype, induces their migration and inhibits their proliferation. Using molecular and cell biology techniques, we will describe the signaling pathway and identify the receptor that mediates elastin's regulation of vsmcs.
Aim 2 : We will study elastin's contribution to the mechanical properties of the murine vascular system. We postulate that elastin deposition determines vessel distensibility or stiffness, and these changes have profound affects on pressure and arterial development. Our preliminary data suggests that as the vessel wall becomes stiffer or less distensible there are compensatory increases in arterial pressure and the number of vsmcs rings that develop around an artery.
Aim 3 : We will determine whether restoring the elastin matrix to a site of arterial injury reduces or prevents obstructive vascular disease. To test its therapeutic potential, we have made elastin sheath-stents and begun to determine whether they reduce coronary restenosis in a porcine model. Together with our previous work, the experiments proposed in this grant application seek to demonstrate that elastin matrix injury is a key step in the pathogenesis of obstructive vascular disease and suggest a novel treatment-elastin therapy.
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