Vascular remodeling is the ability of the vessel wall to reorganize its cellular and extracellular components in response to a chronic stimulus. Work published during the tenure of this grant demonstrated that in response to a chronic change in blood flow, eNOS knockout mice exhibited a paradoxical increase in wall thickness accompanied by an increase in smooth muscle nuclei and proliferation, reminiscent of the changes seen in hypertension and atherosclerosis. New preliminary data show that there is marked upregulation of PDGF BB and survivin, an inhibitor of apoptosis, in abnormally remodeled vessels from eNOS (-I-) mice. In addition we show that during the ontogeny of a remodeling response in normal mice, there is a deficit in basal, but not acetylcholine stimulated endothelium-dependent responses that occurs contemporaneously with cell death in the vessel wall sensing the flow change. These data indicate that impaired endothelium-dependent relaxation of blood vessels, occurs during cellular adaptation to a prolonged remodeling stimulus. With this background in mind, we hypothesize that endothelium-derived NO coordinates hemodynamic changes in the vessel wall to long term structural changes in vessel geometry by influencing fundamental processes that govern apoptosis versus survival, extracellular matrix synthesis and degradation, vascular cell proliferation and migration. As a corollary to this hypothesis, we predict that abnormal vascular remodeling secondary to elevations in plasma cholesterol will be accentuated by the loss of eNOS derived NO. To examine the importance of eNOS derived NO in remodeling the following Specific Aims are proposed:
Aim 1. Define the relationship between eNOS and arterial remodeling in mice;
Aim 2. Examine the mechanistic links between NO, PDGF and survivin in the remodeling process and Aim 3. Elucidate the effects of elevated cholesterol levels on vascular remodeling and vasomotor function. These studies will use a multi-disciplinary approach (cellular, molecular and functional physiology) to understand the importance of eNOS derived NO in vascular remodeling. Results from these studies will assist in our understanding of mechanisms leading to abnormal remodeling in disease with endothelial dysfunction.
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