Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension
Giuseppe Faraco, … , Joseph Anrather, Costantino Iadecola
Giuseppe Faraco, … , Joseph Anrather, Costantino Iadecola
Published November 14, 2016
Citation Information: J Clin Invest. 2016;126(12):4674-4689. https://doi.org/10.1172/JCI86950.
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Research Article Neuroscience Vascular biology

Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension

Abstract

Hypertension is a leading risk factor for dementia, but the mechanisms underlying its damaging effects on the brain are poorly understood. Due to a lack of energy reserves, the brain relies on continuous delivery of blood flow to its active regions in accordance with their dynamic metabolic needs. Hypertension disrupts these vital regulatory mechanisms, leading to the neuronal dysfunction and damage underlying cognitive impairment. Elucidating the cellular bases of these impairments is essential for developing new therapies. Perivascular macrophages (PVMs) represent a distinct population of resident brain macrophages that serves key homeostatic roles but also has the potential to generate large amounts of reactive oxygen species (ROS). Here, we report that PVMs are critical in driving the alterations in neurovascular regulation and attendant cognitive impairment in mouse models of hypertension. This effect was mediated by an increase in blood-brain barrier permeability that allowed angiotensin II to enter the perivascular space and activate angiotensin type 1 receptors in PVMs, leading to production of ROS through the superoxide-producing enzyme NOX2. These findings unveil a pathogenic role of PVMs in the neurovascular and cognitive dysfunction associated with hypertension and identify these cells as a putative therapeutic target for diseases associated with cerebrovascular oxidative stress.

Authors

Giuseppe Faraco, Yukio Sugiyama, Diane Lane, Lidia Garcia-Bonilla, Haejoo Chang, Monica M. Santisteban, Gianfranco Racchumi, Michelle Murphy, Nico Van Rooijen, Joseph Anrather, Costantino Iadecola

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Figure 5

PVM At1r deletion counteracts the harmful cerebrovascular effects of ANGII slow pressor hypertension.

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PVM At1r deletion counteracts the harmful cerebrovascular effects of ANG...
(A) Fourteen weeks after transplant of GFP+ bone marrow in WT mice, GFP+ and CD206+ PVM surrounds GLUT-1+ vessels. Scale bar: 50 μm. (B) By 14 weeks after the transplant, approximately 80% of CD206+ cells in the somatosensory cortex are replaced by GFP+ bone marrow cells. *P < 0.05 vs. 7 weeks group [χ2(1) = 7.78]; n = 5 per group. (C) ANGII increases mean arterial pressure equally in WT mice with transplanted WT bone marrow (WT→WT) or At1r–/– marrow (At1r–/– WT). *P < 0.05 vs. WT→WT–Veh and At1r–/–→WT–Veh; n = 7–10 per group (2-way ANOVA and Bonferroni’s test). (D) At1r deletion in PVMs does not affect the CBF responses to whisker stimulation or ACh, but counteracts the attenuation of both responses induced by ANGII. *P < 0.05 vs. WT→WT–Veh and At1r–/–→WT–Veh; #P < 0.05 vs. WT→WT–ANGII; n = 7–12 per group (2-way ANOVA and Bonferroni’s test).