Hypertension Causes Neural Damage in Part via Altered Macrophage Behavior

The increased blood pressure of age-related hypertension is driven by the stiffening of blood vessels. It harms fragile tissues, such as those of the kidney, directly through the physical processes of greater pressure. It also increases the rate at which small blood vessels suffer structural failure, and in the brain that means an ongoing series of minuscule strokes, each unnoticed, but over time adding up to contribute to cognitive decline. Researchers here outline another mechanism by which hypertension causes harm, in this case via alteration of the behavior of a population of macrophages in the brain, leading to greater levels of oxidative stress and vascular dysfunction. The researchers also show that selectively depleting these macrophages can improve the situation, and thus perhaps form the basis for a therapy:

Hypertension afflicts up to one-third of the world population and is a leading risk factor for morbidity and mortality worldwide. The brain is a major target organ of the damaging effects of hypertension. Well recognized as the most important risk factor for stroke and vascular cognitive impairment, hypertension has also been linked to Alzheimer disease, the leading cause of dementia in the elderly. The health of the cerebrovascular system is vital for the brain's functional and structural integrity. The brain has no energy reserves and requires a continuous supply of blood well matched to its dynamic and regionally diverse metabolic needs. Neurons, glia, and vascular cells, key components of the so-called neurovascular unit (NVU), work in concert to assure that the brain is always adequately perfused. Thus, brain activation increases cerebral blood flow (CBF) to support the increased energy demands and remove potentially harmful by-products of cerebral metabolism, a process known as neurovascular coupling. At the same time, endothelial cells, the site of the blood-brain barrier (BBB), regulate the trafficking of molecules and cells between blood and brain, and coordinate microvascular flow by releasing vasoactive agents. Hypertension leads to profound cerebrovascular alterations. In addition to structural changes (hypertrophy, remodeling, stiffening, lipohyalinosis, etc.), hypertension induces alterations in cerebrovascular regulation that promote vascular insufficiency. Thus, in humans as in animal models, hypertension disrupts all the major factors regulating the cerebral circulation, including neurovascular coupling and endothelial vasomotor function. As a result, the brain becomes more susceptible to neuronal dysfunction and damage, which underlies vascular cognitive impairment

The factors responsible for these functional alterations of the NVU are poorly understood, and their exploration is essential to develop preventative or therapeutic approaches to mitigate the impact of hypertension on brain health. Perivascular macrophages (PVMs) and meningeal and choroid plexus macrophages represent the bulk of resident brain macrophages, and are distinct from macrophages infiltrating the wall of large vessels in inflammatory conditions, such as atherosclerosis. Residing in the intracerebral perivascular space, delimited by the glia limitans and the vascular basement membrane, PVMs are closely apposed to the outer vessel wall and originate from hematopoietic precursors. As the vessels penetrate deeper into the substance of the brain, the glial and vascular basement membranes fuse together and the perivascular space disappears. 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. Brain PVMs are thought to be beneficial in models of Alzheimer disease by removing amyloid-β peptides from the perivascular space and preventing amyloid accumulation in cerebral blood vessels. On the other hand, hypothalamic neurohumoral signaling by PVMs across the BBB may be deleterious by promoting inflammation and sympathetic activation in models of fever or myocardial infarction, respectively, and may contribute to hypertensive cerebrovascular remodeling. In the present study we discovered that PVMs play a key role in the cerebrovascular dysfunction of hypertension. Our data suggest that PVMs, while serving vital homeostatic functions in the normal state, become the target of neurovascular inflammatory signaling leading to reactive oxygen species production, vascular dysfunction, and cognitive deficits. However, the molecular interactions of PVMs with cells of the NVU and their role in the neurovascular dysfunction and BBB alteration remain to be defined.

Link: http://dx.doi.org/10.1172/JCI86950


Wouldn't blood vessels in the brain become damaged over time even without increased blood pressure? It is not like there is a blood pressure below which zero damage occurs right? All this high blood pressure is doing is accelerating a process that is already occuring.

Posted by: Jim at November 15th, 2016 8:21 AM

@Jim: That would look something like a toxicity curve for blood pressure. Probably very non-linear, but I'm sympathetic to the idea that it doesn't go to zero for normal operation. I think that some of the data obtained through blood-pressure-lowering medication might be helpful to that line of thinking, but I'm not sure that those investigators would also be checking useful metrics for blood vessel quality. The quantification of small vessel damage in the brain seems to be a comparatively recent thing; might be better to dig into research on the kidney and blood pressure.

Posted by: Reason at November 15th, 2016 9:15 AM

The article refers to depleting the macrophages as being helpful in preventing decline. How can we do this? Is their something available to individuals that accomplish this?

Posted by: Stephen Cohn at November 23rd, 2016 5:23 PM

@Stephen Cohn: Not yet.

Posted by: Reason at November 23rd, 2016 6:54 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.