From the Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY (M.M.S., S.J.A., D.L., G.F., L.G.-B., G.R., C.P., S.S., S.G.S., J.A., C.I.).
University Medical Center Hamburg-Eppendorf, Hamburg, Germany (J.K.).
Hypertension. 2020 Sep;76(3):795-807. doi: 10.1161/HYPERTENSIONAHA.120.15581. Epub 2020 Jul 13.
Hypertension is a leading cause of stroke and dementia, effects attributed to disrupting delivery of blood flow to the brain. Hypertension also alters the blood-brain barrier (BBB), a critical component of brain health. Although endothelial cells are ultimately responsible for the BBB, the development and maintenance of the barrier properties depend on the interaction with other vascular-associated cells. However, it remains unclear if BBB disruption in hypertension requires cooperative interaction with other cells. Perivascular macrophages (PVM), innate immune cells closely associated with cerebral microvessels, have emerged as major contributors to neurovascular dysfunction. Using 2-photon microscopy in vivo and electron microscopy in a mouse model of Ang II (angiotensin II) hypertension, we found that the vascular segments most susceptible to increased BBB permeability are arterioles and venules >10 µm and not capillaries. Brain macrophage depletion with clodronate attenuates, but does not abolish, the increased BBB permeability in these arterioles where PVM are located. Deletion of AT1R (Ang II type-1 receptors) in PVM using bone marrow chimeras partially attenuated the BBB dysfunction through the free radical-producing enzyme Nox2. In contrast, downregulation of AT1R in cerebral endothelial cells using a viral gene transfer-based approach prevented the BBB disruption completely. The results indicate that while endothelial AT1R, mainly in arterioles and venules, initiate the BBB disruption in hypertension, PVM are required for the full expression of the dysfunction. The findings unveil a previously unappreciated contribution of resident brain macrophages to increased BBB permeability of hypertension and identify PVM as a putative therapeutic target in diseases associated with BBB dysfunction.
高血压是中风和痴呆的主要原因，其影响归因于破坏大脑的血液供应。高血压还会改变血脑屏障（BBB），这是大脑健康的关键组成部分。尽管内皮细胞最终负责 BBB，但屏障特性的发展和维持取决于与其他血管相关细胞的相互作用。然而，目前尚不清楚高血压中 BBB 的破坏是否需要与其他细胞的协同相互作用。周细胞（PVM），与脑微血管密切相关的固有免疫细胞，已成为神经血管功能障碍的主要贡献者。我们使用活体双光子显微镜和 Ang II（血管紧张素 II）高血压小鼠模型中的电子显微镜，发现血管段中最易发生 BBB 通透性增加的是 10 µm 以上的小动脉和小静脉，而不是毛细血管。用 clodronate 耗尽脑巨噬细胞可减轻，但不能消除这些小动脉中 PVM 所在部位的 BBB 通透性增加。骨髓嵌合体中 PVM 上的 AT1R（血管紧张素 II 型 1 受体）缺失部分通过产生自由基的酶 Nox2 减轻了 BBB 功能障碍。相比之下，使用基于病毒基因转移的方法下调脑内皮细胞中的 AT1R 可完全防止 BBB 破坏。结果表明，虽然内皮细胞 AT1R 主要在小动脉和小静脉中引发高血压中的 BBB 破坏，但 PVM 是功能障碍完全表达所必需的。这些发现揭示了驻留脑巨噬细胞对高血压 BBB 通透性增加的先前未被认识的贡献，并确定 PVM 是与 BBB 功能障碍相关疾病的潜在治疗靶点。
