Cerebrovascular changes in pregnancy and hypertension

描述（由申请人提供）：子痫是一种严重的妊娠并发症，发生于妊娠期高血压发展为神经系统并发症时，包括头痛、呕吐、失明和惊厥。虽然妊娠期高血压会影响多个器官，但脑血管受累是约40%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与高血压脑病相似，其中压力的急性升高引起自动调节突破、过度灌注和水肿。我们的初步研究发现，晚期妊娠动物在急性高血压期间与非妊娠动物相比，脑血管阻力和过度灌注显著降低，类似于子痫。重要的是，只有晚期妊娠的动物发生脑水肿，这表明当血压升高时，妊娠本身使大脑易于发生子痫的神经系统并发症。由于水肿形成在介导子痫的神经系统并发症中的突出作用，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，从而在血压升高期间促进静水性脑水肿。我们的初步研究首次表明，怀孕会导致脑小动脉的向外重塑，这种影响可能会减少急性高血压期间大脑中小血管的阻力。因此，目的1将调查潜在的机制，怀孕引起外向重塑，包括激素松弛素，已知促进血管重塑在怀孕期间的体循环。我们还发现，与未怀孕的动物相比，怀孕导致更严重的血脑屏障破坏，以应对急性高血压。目的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，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女性在发生导致神经系统并发症的急性高血压事件之前就已存在高血压或先兆子痫，因此目标3将使用妊娠高血压模型来研究脑血流动力学，血脑屏障特性和水肿形成的变化，这些变化与正常妊娠相比可能是独特的。将使用体内和体外技术的强大组合，提供关于妊娠期间水肿和妊娠高血压的新型血流动力学变化和机制的临床相关信息。公共卫生相关性：子痫是全球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影响脑循环的潜在机制，这些机制促进了子痫的神经系统并发症。这种理解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.