UC San Diego

Recent evidence suggests that endothelial apoptosis may be a mechanism for capillary rarefaction in hypertensives. The objective of this study is to examine the early phase of cell apoptosis and capillary blood flow in single capillaries of the rat mesentery in the spontaneously hypertensive rat (SHR) and its normotensive control, the Wistar-Kyoto (WKYs) rat. Since hypertension in the SHR is critically dependent on glucocorticoids, the animals were treated with a synthetic glucocorticoid, dexamethasone (DEX), by intraperitoneal injection and by superfusion. Capillaries with single file flow of cells in mesentery were observed in-vivo at high resolution during a period of that leads to permanent stasis without central pressure reduction. Propidium iodide (PI) was used as a marker to detect apoptosis. Continuous observation of apoptotic cells showed that permanent stasis in capillaries is initiated by the entrapment of leukocytes at the location of an endothelial cell that had platelets attached to its membrane. The capillary endothelial cell at which such obstruction occurred may or may not be PI-positive, but after stasis became PI-positive followed by apoptosis in other endothelial cells of the same obstructed capillary. No increase in endothelial cell apoptosis was seen in capillaries without stasis, and no stasis occurred in arterioles and venules with diameters larger than capillaries and continued flow. The stasis occurred without detectable reduction in central blood pressure or arteriolar constriction. The incidence of permanent capillary stasis and total cell death in the WKY+DEX group is significantly higher than that of untreated control group, WKY, whereas there were no differences between the SHR+DEX and the SHR. Blockade of the lectin domain of L- selectin or a platelet membrane adhesion molecule (glycoprotein IIb/IIIa) blocked the development of stasis. The current in-vivo results indicate that (1) glucocorticoid, which is involved in the development of hypertension, also facilitates cell death and microvessel stasis, (2) the presence of immobilized platelets and leukocytes plays a central role in capillary stasis, and (3) capillary stasis leads to progression of endothelial apoptosis along the entire length of the capillary