Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension

Abstract

In this study we investigated the contribution of PVMs to the neurovascular and cognitive dysfunction induced by hypertension. We found that depletion of PVMs in models of chronic hypertension suppresses vascular oxidative stress and ameliorates the attendant impairment in neurovascular coupling and endothelium-dependent responses. Studies in bone marrow (BM) chimeras provided evidence that the dysfunction is mediated by ANGII acting on PVM AT1Rs resulting in NOX2-dependent ROS production. Importantly, concomitant to the neurovascular improvement, PVM depletion also rescued cognitive dysfunction. The findings unveil a previously unrecognized role of PVMs in the neurovascular and cognitive dysfunction induced by hypertension, and identify PVMs as a novel pathogenic component of the NVU of critical importance for brain health.

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

“…Importantly, lower plasma concentrations of HDL were reported to be associated with dementia (45). Considering that BBB leakage for small-size molecules (angiotensin II) can lead to cognitive defects (30), attenuated HDL/S1P 1 -dependent tightening of the BBB may be a risk factor for dementia. A recent study also demonstrated that BBB disruption is selective for small-size molecules at the early phase of murine ischemic brain injury (46).…”

“…Of note, chronic, but not acute, hypertension increases BBB leakage for small molecules, which causes cognitive impairment by enhancing exposure of angiotensin II to perivascular macrophage (30). Therefore, we asked whether deletion of endothelial S1pr1 and after BBB opening can affect recognition memory.…”

Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice

“…In addition, analysis showed a non-linear correlation between hippocampal TNF-α and blood pressure, suggesting that other factors could modulate the association between these parameters. For example, the breakdown of the bloodbrain barrier (BBB) induced by Ang II may be involved in the inflammatory process [31,32]. Indeed, a study from Marvar showed that Ang II is critical for BBB damage, independently of blood pressure [31].…”

“…Therefore, it is likely that the cerebral inflammation induced by Ang II involves multiple pathways and cellular players, including but not limited to (i) the direct effects of circulating Ang II on AT1 receptors in cerebral vessels [51]; (ii) the damage to the BBB [32], which could facilitate the entry of Ang II to brain regions beyond the CVO network (i.e., the hippocampus); (iii) the consequent effects on microglia and astrocytes, leading to the expression of pro-inflammatory cytokines within the brain; and (iv) the entry of activated immune cells from the periphery.…”

Macrophages come to mind as keys to cognitive decline

“…In this issue, Faraco et al provide an exciting link between hypertension and cognitive decline (15). Specifically, they have shown that perivascular macrophages (PVMs) closely associate with cortical arterioles and that hypertension causes disruption of the blood-brain barrier, allowing Ang II to reach these cells.…”