Transfer request of grant 1R21MH119561-01A1 (Deslauriers, Jessica) to Laval University

创伤后应激障碍（PTSD）患者的心血管风险增加。然而，在这方面， 心血管风险/高血压和PTSD之间的因果关系尚不清楚， PTSD与心血管疾病的高共病率的潜在机制还不清楚。 有证据表明，常用的针对肾素的降压药物的作用- 血管紧张素系统不仅可以降低血压，还可以对创伤有治疗作用， 相关疾病，如PTSD。血管紧张素II（Ang II）信号通过Ang-II型 1受体（AT 1 R）影响创伤反应和症状尚不清楚。Ang-II在严重时释放 有一些证据表明，中央AT 1aRs可能通过直接影响恐惧而影响PTSD 电路激活然而，另一种机制是外周血管紧张素II信号也可能有助于 通过破坏中枢神经系统暴露于炎症信号而发展PTSD 血脑屏障（BBB）在创伤过程中和创伤后。血脑屏障，作为主要的屏障， 外周和中枢系统，在调节中枢稳态中至关重要。BBB完整性被破坏， 高血压和严重的压力，并与最强的创伤相关的危险因素之一， 创伤后应激障碍，脑外伤。Gq信号的AT 1 R活化破坏内皮细胞的紧密连接， 允许蛋白质等大分子通过。在这里，我们提出，严重的压力增加， 外周血管紧张素II，激活内皮AT 1受体，导致血压升高和血脑屏障 磁导率创伤诱导的血脑屏障破坏可能使外周炎性细胞进入， 向大脑发送信号分子，增加患创伤后应激障碍的风险我们建议通过使用细胞来测试这个假设- 类型特异性遗传和化学工具，以探测外周AT 1aR信号传导对持久 对创伤的中枢炎症和行为反应。目的1将检验外周AT 1aR 信号传导对于创伤诱导的持久中枢炎症PTSD样行为的增加是必需的。目的 2将检验创伤期间和创伤后内皮细胞中的Gq/11信号传导足以破坏 血脑屏障完整性和增加持久的炎症和行为反应的创伤。因此，拟议的 研究将确定外周和中枢肾素-血管紧张素系统之间的关系， 增加中枢免疫信号传导和持久的创伤症状，并提供有关 BBB通透性对创伤风险和症状维持的影响。

There is an increased cardiovascular risk in individuals with posttraumatic stress disorder (PTSD). However, the causal relationship between cardiovascular risk/hypertension and PTSD remains unclear, and the mechanisms underlying the high comorbidity of PTSD with cardiovascular diseases are not well understood. Evidence suggests that the actions of commonly used blood pressure medications that target the renin- angiotensin system extend beyond blood pressure reduction and may have therapeutic effects on trauma- related disorders, such as PTSD. The mechanisms for how angiotensin II (Ang II) signaling through Ang-II type 1 receptors (AT1R) affects trauma response and symptoms are not clear. Ang-II is released during severe stress, and there is some evidence for central AT1aRs to potentially affect PTSD through direct effects on fear circuit activation. An alternate mechanism however is that peripheral Ang II signaling may also contribute to development of PTSD through exposure of the central nervous system to inflammatory signaling via disruption of the blood brain barrier (BBB) during and after trauma. The BBB, by being the primary barrier separating the peripheral and central systems, is crucial in the regulation of central homeostasis. BBB integrity is disrupted by hypertension and severe stress, and is associated with one of the strongest trauma-related risk factors for PTSD, traumatic brain injury. AT1R activation of Gq signaling disrupts the tight junctions of endothelial cells, allowing larger molecules such as proteins to pass through. Here we propose that severe stress increases peripheral Ang II, which activates endothelial AT1Rs, leading to both increased blood pressure and BBB permeability. The trauma-induced BBB breakdown may then enable access of peripheral inflammatory signaling molecules to the brain, increasing the risk for PTSD. We propose to test this hypothesis by using cell- type specific genetic and chemogenic tools to probe the contribution of peripheral AT1aR signaling to enduring central inflammatory and behavioral responses to trauma. Aim 1 will test the hypothesis that peripheral AT1aR signaling is necessary for trauma-induced increases in enduring central inflammation PTSD-like behavior. Aim 2 will test the hypothesis that Gq/11 signaling in endothelial cells during and after trauma is sufficient to disrupt BBB integrity and increase enduring inflammatory and behavioral responses to trauma. Thus, the proposed studies will identify the relationship between peripheral and central renin-angiotensin system to lead to increased central immune signaling and enduring trauma symptoms, and provide insights into the contribution of BBB permeability to trauma risk and symptom maintenance.