2. Cardiovascular and Cerebrovascular Aging. During the aging process, functional and structural abnormalities occur in the vasculature that may predispose humans to cardiovascular disease. Vascular remodeling duringaging is associated with an increase in oxidative stress which may activate pro-inflammatorypathways, resulting in thedevelopment of vascular pathologies similar to those observed duringatherogenesis. The pathogenesis of these agemediated vascular abnormalities is notwell understood. The long-term goal of our research is to establish the cellular and molecular basis for the aberrant vascular remodeling during aging that predisposesthe vasculature to disease and results in pathologicalrather than compensatory adaptations in response to various stimuli. This study will identifymolecular pathways whose genetic regulation is altered dudng aging and that contribute to age-dependent vascular remodeling. Our preliminary data indicatethat vascular pathologies in the rat develop progressively with age, as in humans, and that gene and protein expression is affected in an age-dependent manner. These pathologies appear to vary in extent and type with the strain of rat and between different types of vessels. Hypothesis: A progressiveincrease in oxidative stress activates inflammatory pathways, which then produce the aberrant remodeling observed with aging.
Specific Aim 1 : Conduct a survey of inbred rat strains and specific artery types to identifytwo strains and two artery types within strains that demonstrate minimal and maximal degrees of age-dependent vascular remodeling.
Specific Aim 2 : Perform microarray analysis to identifygenes whose increased or decreased expression is correlated with vascular aging, with special attention to inflammatory mediators. Strains and vessels with and without substantial vascular aging will be selected from the results of aim 1.
Specific Aim 3 : Elucidate pathways and moleculeswith potential interactions that may mediate progressive vascular aging with the objectiveof developing therapies for prevention and treatment of age-related vascular pathologies. Identifying novel pathways that regulate gene expression during progressivevascular aging will both extend our understanding of age-dependent vascular pathology and promote the development of therapies for the prevention and treatment of age-related cardiovascular disease. This is especially relevant in light of the fact that the majority of pharmaceuticals currently in use were developed for treatment of young, and not aged, adults, who represent an increasing proportion of the population.
| Sheridan, Kevin M; Ferguson, Michael J; Distasi, Matthew R et al. (2007) Impact of genetic background and aging on mesenteric collateral growth capacity in Fischer 344, Brown Norway, and Fischer 344 x Brown Norway hybrid rats. Am J Physiol Heart Circ Physiol 293:H3498-505 |
