Aging is associated with profound alterations in vascular structure and function that may underlie the vascular disease that frequently accompanies the aging process. The overall hypothesis of this project is that alterations in microvascular reactivity associated with aging is related to quantitative differences in the extracellular matrix (ECM) proteins in the vascular wall and to alterations in integrin-mediated regulation of vascular tone. Recent evidence from our laboratories supports a novel role for integrins and the extracellular matrix in the control of vasomotor tone. These studies indicate stimulation of vascular smooth muscle or endothelial integrins can lead to pronounced changes in vascular tone. In addition, preliminary data indicate that both oxidative stress and hypertension, both of which often accompany the aging process, alter the expression of both ECM proteins and their integrin receptors. The goal of this proposal is to determine if alterations in ECM proteins and/or integrins contribute to the changes in vasomotor responsiveness seen in aging. This project will utilize Fisher 344 rats of varying ages as an experimental model for aging. Assessments of will be made of the expression of extracellular matrix proteins, integrins, and matrix metalloproteinases in small arteries and arterioles from young, middle age, old and very old rats. We will also examine the vascular reactivity of arterial vessels to soluble and insoluble integrin-binding ligands in the various age groups. Our strategy is to combine data from intact vessels, biochemical and molecular approaches will provide a powerful approach for testing our hypothesis and systematically integrating our results.
The specific aims of this proposal are:
Aim 1 : Compare extracellular matrix composition and integrin expression in young, middles age, old and very old rats and to determine if there are differences and to examine the activity and expression of matrix degrading proteases between differently aged groups.
Aim 2 : Compare the ECM-integrin dependent alterations in vasomotor responses of arterial vessels from young, middle age, old and very old rats. Synthetic peptides with known integrin-binding motifs as well as enzymatically generated fragments of extracellular matrix proteins (e.g. collagen type I) will be utilized in these studies to assess integrin-mediated changes in microvascular reactivity. Collectively, these studies will provide new insight that will advance our understanding of the relationship between changes in vascular structure associated with aging and blood vessel function with respect to control of vascular tone.
