Cerebrovascular Changes in Pregnancy and Hypertension

描述(申请人提供)：子痫是妊娠的一种严重并发症，当高血压发展成神经系统症状时发生，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，但脑血管受累是大约40%的患者死亡的直接原因。发生的主要脑血管变化被证明类似于高血压脑病，在这种疾病中，急性血压升高(即急性高血压)克服了脑动脉和小动脉的肌源性血管收缩，导致自我调节衰竭、过度灌流和水肿。由于患有子痫的女性通常在怀孕前血压正常，因此有证据表明，怀孕影响大脑循环的方式使血管在急性高血压期间容易受到自我调节衰竭和过度灌流的影响。这项建议的长期目标是调查怀孕如何影响大脑循环的结构和功能，重点是直径调节对压力变化(肌源性反应性)的反应，以及这些变化如何影响促进水肿的血管通透性。目的1利用妊娠和非妊娠大鼠的分离和加压大脑后动脉来确定发生强迫扩张的压力，并探讨妊娠引起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(如一氧化氮和前列腺素)。此外，由于高血压本身已被证明会导致大脑循环中显著的重塑和反应性变化，目标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的肌源性活动和直径调节(一氧化氮抑制)。急性高血压和子痫与由于正常不通透性脑内皮细胞的破坏而导致的明显的水肿形成有关。因此，AIM 2将研究急性高血压期间妊娠引起的内皮细胞通透性的变化，包括液体相内吞作用(跨细胞通量)和紧密连接中断(细胞旁通量)。在强制扩张过程中，妊娠对通透性的影响将使用包括清除荧光示踪剂和透射电子显微镜在内的多种技术相结合来确定。

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.