Cerebrovascular Changes in Pregnancy and Hypertension

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DESCRIPTION (provided by applicant): Eclampsia is a serious complication of pregnancy that occurs when hypertension develops with neurologic symptoms, including headaches, nausea, visual disturbances and convulsions. While numerous organs are affected by hypertension in pregnancy, cerebrovascular involvement is the direct cause of death in approximately 40 percent of patients. The major cerebrovascular changes that occur have been shown to be similar to hypertensive encephalopathy in which acute elevations in blood pressure (i.e., acute hypertension) overcome the myogenic vasoconstriction of the cerebral arteries and arterioles causing autoregulatory failure, hyperperfusion and edema. Because women who develop eclampsia in general are normotensive prior to pregnancy, there is evidence that pregnancy affects the cerebral circulation in a way that makes the vessels susceptible to autoregulatory failure and hyperperfusion during acute hypertension. The long-term objective of this proposal is to investigate how pregnancy affects the structure and function of the cerebral circulation focusing on diameter regulation in response to changes in pressure (myogenic reactivity) and how those changes affect vascular permeability that promotes edema. Aim 1 will use isolated and pressurized posterior cerebral arteries from pregnant and nonpregnant rats to determine the pressure at which forced dilatation occurs and investigate underlying mechanisms of pregnancy-induced alterations in diameter regulation, including vascular smooth muscle actin and endothelial cell influences (e.g., nitric oxide and prostaglandins). In addition, since hypertension alone has been shown to cause significant remodeling and reactivity changes in the cerebral circulation, Aim 1 will also investigate how elevated mean arterial pressure during pregnancy affects myogenic activity and diameter regulation in a rat model of hypertension in pregnancy (nitric oxide inhibition). Acute hypertension and eclampsia are associated with significant edema formation due to disruption of the normally impermeable cerebral endothelium. Therefore, Aim 2 will investigate pregnancy-induced changes in endothelial cell permeability during acute hypertension, including enhanced fluid phase endocytosis (transcellular flux) and tight junction disruption (paracellular flux). The influence of pregnancy on permeability during forced dilatation will be determined using a combination of techniques, including clearance of fluorescent tracers and transmission electron microscopy.