Endothelium-Macrophage Crosstalk Mediates Blood-Brain Barrier Dysfunction in Hypertension.
Hypertension
; 76(3): 795-807, 2020 09.
Article
en En
| MEDLINE
| ID: mdl-32654560
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Arteriolas
/
Encéfalo
/
Endotelio Vascular
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Barrera Hematoencefálica
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Circulación Cerebrovascular
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Receptor de Angiotensina Tipo 1
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Hipertensión
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Macrófagos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Hypertension
Año:
2020
Tipo del documento:
Article