Cerebrovascular changes in pregnancy and hypertension

描述(申请人提供)：子痫是妊娠期的一种严重并发症，当妊娠期高血压发生时，会出现神经系统并发症，包括头痛、呕吐、失明和抽搐。妊娠期高血压可累及多个器官，而脑血管受累是40%的患者死亡的直接原因。在子痫期间发生的主要脑血管变化被认为类似于高血压性脑病，在这种疾病中，压力的急剧升高会导致自我调节突破、过度灌流和水肿。我们的初步研究发现，与未怀孕的动物相比，妊娠晚期的动物在急性高血压期间显著降低了脑血管阻力和高灌注量，类似于子痫。重要的是，只有怀孕后期的动物才出现脑水肿，这表明当血压升高时，怀孕本身就会使大脑容易出现子痫的神经并发症。由于水肿形成在调节子痫的神经系统并发症中的突出作用，该项目的长期目标是了解怀孕和妊娠期高血压通过一种方式影响大脑循环的潜在机制，这种方式在血压升高时促进水静止性脑水肿。我们的初步研究首次表明，怀孕会导致大脑小动脉的外向重塑，这一影响可能会在急性高血压期间减少大脑中的小血管阻力。因此，目标1将调查怀孕引起外向重塑的潜在机制，包括已知促进怀孕期间体循环血管重塑的激素松弛素。我们还发现，与未怀孕的动物相比，怀孕会导致更严重的血脑屏障破坏，以应对急性高血压。目标2将研究发生这种情况的潜在机制，包括胎盘生长因子的产生，它可以增加水力传导性和减少紧密连接的表达。最后，由于许多患有子痫的妇女在导致神经系统并发症的急性高血压事件之前就已经存在高血压或先兆子痫，Aim 3将使用妊娠高血压模型来研究与正常妊娠相比可能是独一无二的脑血流动力学、血脑屏障特性和水肿形成的变化。将使用体内和体外技术的强大组合，这些技术应该提供关于妊娠期间水肿和妊娠期高血压的新的血流动力学变化和机制的临床相关信息。与公共卫生相关：子痫是全世界孕产妇死亡的主要原因。这些研究探讨了怀孕和妊娠期高血压影响大脑循环的潜在机制，这些机制促进了子痫的神经并发症。这一认识对于有效管理和治疗这种毁灭性的疾病至关重要。

DESCRIPTION (provided by applicant): Eclampsia is a serious complication of pregnancy that occurs when hypertension during pregnancy develops with neurologic complications, including headache, vomiting, blindness and convulsions. While multiple organs are affected by hypertension in pregnancy, cerebrovascular involvement is the direct cause of death in ~40% of patients. The major cerebrovascular changes that occur during eclampsia are thought to be similar to hypertensive encephalopathy in which acute elevations in pressure cause autoregulatory breakthrough, hyperperfusion and edema. Our preliminary studies found that late-pregnant animals had significantly decreased cerebrovascular resistance and hyperperfusion compared to nonpregnant animals during acute hypertension, similar to eclampsia. Importantly, only the late-pregnant animals developed cerebral edema, suggesting that pregnancy alone predisposes the brain to the neurologic complications of eclampsia when blood pressure is elevated. Because of the prominent role of edema formation in mediating the neurologic complications of eclampsia, the long-term objective of this project is understand the underlying mechanisms by which pregnancy and hypertension in pregnancy affect the cerebral circulation in a way that promotes hydrostatic brain edema during increased blood pressure. Our preliminary studies suggest for the first time that pregnancy causes outward remodeling of cerebral arterioles, an effect that likely diminishes small vessel resistance in the brain during acute hypertension. Aim 1 will therefore investigate underlying mechanisms by which pregnancy causes outward remodeling, including the hormone relaxin, known to promote vascular remodeling in the systemic circulation during pregnancy. We also found that pregnancy causes more severe blood-brain barrier disruption in response to acute hypertension compared to nonpregnant animals. Aim 2 will investigate underlying mechanisms by which this occurs, including production of placental growth factor that can increase hydraulic conductivity and decrease tight junction expression. Lastly, because many women who develop eclampsia have preexisting hypertension, or preeclampsia, prior to the acute hypertensive event that causes neurologic complications, Aim 3 will use a model of hypertension in pregnancy to investigate changes in cerebral hemodynamics, blood-brain barrier properties and edema formation that may be unique compared to normal pregnancy. A powerful combination of in vivo and in vitro techniques will be used that should provide clinically relevant information regarding novel hemodynamic changes and mechanisms of edema during pregnancy and hypertension in pregnancy. PUBLIC HEALTH RELEVANCE: Eclampsia is a leading cause of maternal death world-wide. These studies investigate underlying mechanisms by which pregnancy and hypertension during pregnancy affect the cerebral circulation in ways that promote the neurologic complications of eclampsia. This understanding is crucial to effective management and treatment of this devastating condition.