Hypertension is associated with a significantly increased risk for vascular lesions, microvascular complications and end organ failure. Our objective is to explore in experimental models of arterial hypertension basic mechanisms that lead to inflammation and tissue injury at the microvascular level. Our previous results indicate a significant enhancement of microvascular oxidative stress in several models of hypertension. We hypothesize that hypertensives have enhanced levels of microcirculatory apoptosis with arteriolar and capillary rarefaction, a shift in the expression of enzyme profiles producing reactive oxygen species and an abnormal leukocyte-endothelial cell membrane interaction.
Our Specific Aims are (a) to examine in-vivo in the microcirculation of selected tissues the mechanisms of apoptosis in endothelial cells and adjacent parenchymal cells as basis for microvascular rarefaction; (b) to identify the mechanisms for the enhanced oxidative stress in hypertensives and its influence on apoptosis in the microcirculation; and (c) to examine the molecular basis for abnormal adhesion of leukocytes to microvascular endothelium in hypertension and its impact on apoptosis in form of membrane adhesion molecule expression and targeted blockade of leukocyte adhesion molecules. The studies will be carried out within the context of a complete microcirculation, including high and low pressure regions, and identify pressure and non-pressure mediate organ injury mechanisms. We will utilize state-of-the-art digital fluorescent intravital microscopy to generate in-vivo records of apoptosis in microvessels. We will exploit recently developed techniques to display mRNA and protein levels within a microvascular network in order to uncover mechanisms of inflammation that promote apoptosis. The hypertensive state in the spontaneously hypertensive rat will be controlled by depletion and supplementation of adrenal hormones and in the Dahl hypertensive rats by dietary salt enhancement. These studies serve to delineate mechanisms for the expression of key inflammatory mediators in hypertensive microvessels as a basis for development of new interventions against the injurious aspects of this syndrome.
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