Cerebrovascular Changes in Pregnancy and Hypertension

描述（由申请人提供）：子痫是妊娠的一种严重并发症，发生在高血压并发神经系统症状时，包括头痛、恶心、视力障碍和抽搐。虽然妊娠期高血压会影响许多器官，但脑血管病变是约40%患者死亡的直接原因。发生的主要脑血管变化已被证明与高血压脑病相似，其中血压的急性升高（即急性高血压）克服了脑动脉和小动脉的肌源性血管收缩，导致自身调节功能衰竭、高灌注和水肿。因为患有子痫的女性在怀孕前血压一般都是正常的，有证据表明，怀孕会影响大脑循环，使血管在急性高血压期间容易发生自我调节功能衰竭和高灌注。这项提议的长期目标是研究妊娠如何影响脑循环的结构和功能，重点是直径调节，以响应压力的变化（肌源性反应），以及这些变化如何影响血管通透性，促进水肿。目的1将使用怀孕和未怀孕大鼠的分离和加压的大脑后动脉来确定发生强迫扩张的压力，并研究妊娠诱导的直径调节改变的潜在机制，包括血管平滑肌肌动蛋白和内皮细胞的影响（例如，一氧化氮和前列腺素）。此外，由于高血压本身已被证明会引起显著的脑循环重塑和反应性变化，Aim 1还将研究妊娠期平均动脉压升高如何影响妊娠期高血压大鼠模型（一氧化氮抑制）的肌生成活动和直径调节。急性高血压和子痫与严重水肿的形成有关，这是由于正常情况下不可渗透的脑内皮破坏所致。因此，Aim 2将研究妊娠引起的急性高血压期间内皮细胞通透性的变化，包括增强的流体期内吞作用（细胞外通量）和紧密连接破坏（细胞旁通量）。妊娠对强迫扩张期间通透性的影响将使用多种技术来确定，包括清除荧光示踪剂和透射电子显微镜。

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.