The cellular and molecular factors regulating blood flow during human brain development or in association with hypertension, infarction and stroke are not well-studied. Our five year plan will reveal whether pericytes (PC), in association with vascular endothelial cells (EC), control microvascular tone using contractile and cytoskeletal proteins. We will use cytoskeletal-specific markers in conjunction with light and electron microscopy to localize PC, EC and vascular smooth muscle in ultrathin frozen and plastic-embedded thin sections prepared from the cerebral cortex, basal ganglia, thalamus, cerebellum, pons and spinal cord of spontaneously hypertensive (SHR) and normal (Wistar-Kyoto, WKY) rat brains during normal development and following the onset of cerebrovascular disease. These results will be compared to data derived from the in situ characterization of microvascular cells present in necropsy materials obtained from normal humans and the victims of infarction and stroke. Vascular cell response to injury will be studied in the SHR and WKY after middle cerebral arterial occlusion and trauma. These results will reveal PC and EC expression during the angiogenesis accompanying cerebral ischemia, inflammation and injury. SHR and WKY cerebral microvascular cells will be isolated and characterized in vitro. Requirements for PC and EC contraction will be revealed using a computer-assisted phase contrast light microscope interfaced with a time-lapse videotape recording system. Vasoactive amine modulation of SHR vs. WKY PC and EC contractile potential and protein expression in specific microvascular beds will be quantitated. Coordination of microvascular tone via EC-PC gap junctions will be examined as a function of SHR and WKY brain development and through the onset of hypertension and stroke. The results to these fundamental in situ and in vitro experiments may ultimately reveal the basic, cellular mechanisms controlling the anomalous flow of blood seen in association with human cerebrovascular disorders.
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