Cerebrovascular changes in pregnancy and hypertension

描述（由申请人提供）：子痫是妊娠期高血压并发神经系统并发症，包括头痛、呕吐、失明和抽搐时发生的一种严重妊娠并发症。妊娠期高血压可累及多器官，其中脑血管累及是约40%患者死亡的直接原因。子痫期间发生的主要脑血管变化被认为与高血压性脑病相似，高血压性脑病的急性血压升高导致自身调节突破、高灌注和水肿。我们的初步研究发现，与未怀孕的动物相比，孕晚期动物在急性高血压期间脑血管阻力和高灌注明显降低，类似于子痫。重要的是，只有怀孕后期的动物出现了脑水肿，这表明当血压升高时，怀孕本身就容易使大脑产生子痫的神经系统并发症。由于水肿形成在介导子痫神经系统并发症中的重要作用，本项目的长期目标是了解妊娠和妊娠期高血压影响脑循环的潜在机制，从而在血压升高时促进流体静力性脑水肿。我们的初步研究首次表明，怀孕导致脑小动脉向外重塑，这种影响可能会降低急性高血压期间大脑小血管的阻力。因此，目的1将研究妊娠引起外展重塑的潜在机制，包括激素松弛素，已知在妊娠期间促进体循环血管重塑。我们还发现，与未怀孕的动物相比，怀孕导致急性高血压更严重的血脑屏障破坏。目的2将研究这种情况发生的潜在机制，包括胎盘生长因子的产生，胎盘生长因子可以增加水力传导性和减少紧密连接的表达。最后，由于许多发生子痫的妇女在急性高血压事件（引起神经系统并发症）之前就已经存在高血压或子痫前期，Aim 3将使用妊娠期高血压模型来研究与正常妊娠相比可能独特的脑血流动力学、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有力结合，为妊娠期水肿和妊娠期高血压的新血流动力学变化和机制提供临床相关信息。公共卫生相关性：子痫是全世界孕产妇死亡的主要原因。这些研究探讨了妊娠和妊娠期高血压以促进子痫神经系统并发症的方式影响脑循环的潜在机制。这一认识对于有效管理和治疗这种毁灭性疾病至关重要。

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.