Endothelium-Macrophage Crosstalk Mediates Blood-Brain Barrier Dysfunction in Hypertension
| Autor: | Giuseppe Faraco, Sung Ji Ahn, Josef Anrather, Jakob Körbelin, Costantino Iadecola, Carrie Poon, Samantha Schaeffer, Gianfranco Racchumi, Steven G. Segarra, Lidia Garcia-Bonilla, Monica M Santisteban, Diane A. Lane |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Endothelium Blood–brain barrier Receptor Angiotensin Type 1 Article Capillary Permeability 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation In vivo Internal Medicine Medicine Animals Cognitive Dysfunction Receptor Innate immune system business.industry Macrophages Brain Angiotensin II Cell biology Arterioles Disease Models Animal 030104 developmental biology medicine.anatomical_structure Cerebral blood flow Blood-Brain Barrier Cerebrovascular Circulation Hypertension cardiovascular system Endothelium Vascular business Glymphatic System 030217 neurology & neurosurgery |
| Zdroj: | Hypertension |
| ISSN: | 1524-4563 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|