The Role of the Hippocampal Vasculature in Vascular Cognitive Impairment and Dementia

Chronic hypertension affects over 100 million adults in the US and is a major risk factor for cerebrovascular
disease and vascular cognitive impairment (VCI). VCI involves impairment in multiple cognitive domains, often
affecting the hippocampus and memory function leading to dementia. The hippocampus is a deep brain structure
that is central to learning and memory and particularly susceptible to injury. Perfusion of the hippocampus is
maintained by small hippocampal arterioles (HAs) that are critical to both basal- and activity-dependent changes
in blood flow. Cognitive decline occurs more rapidly in the setting of chronic hypertension compared to normal
aging; however, how chronic hypertension and aging affect HAs remains unclear and could contribute to VCI.
The goal of this proposal is to investigate the novel role of HAs in healthy cognitive aging and VCI associated
with chronic hypertension. Our preliminary and published data show that HAs were hyperconstricted and had
impaired vasodilatory function in a rat model of chronic hypertension. Further, hippocampal perfusion was
significantly reduced and memory impaired during chronic hypertension that occurred as a function of age.
Importantly, HA dysfunction preceded these changes in perfusion and memory function, suggesting
hypertension-induced memory decline is vascular in nature. Our central hypothesis is that chronic hypertension
progressively decreases the vasodilatory function of HAs that reduces resting and activity-dependent changes
in hippocampal perfusion, resulting in neuronal injury and VCI. Aim 1 will investigate HA endothelial and vascular
smooth muscle function, including vasoconstrictive and vasodilatory pathways, in normotensive and
hypertensive rats by studying isolated and pressurized HAs in vitro. Circulating potent vasoconstrictors (e.g.
angiotensin II, endothelin-1, tumor necrosis factor alpha) that are elevated during chronic hypertension and
cause oxidative stress and damage endothelium will be investigated as underlying mechanisms by which chronic
hypertension causes hyperconstriction and impaired vasodilation of HAs. Aim 2 will investigate progressive
changes in hippocampal perfusion and neurovascular coupling – the innate ability of the brain to increase local
blood flow in response to neuronal activity – as it relates to neuronal function and memory in normotensive and
hypertensive rats across the lifetime. We will determine the role of HAs in age- and hypertension-induced
changes in hippocampal hemodynamics by investigating if therapeutically improving HA function prevents
perfusion deficits, protects hippocampal neurons and slows cognitive decline to be similar to normal aging. This
proposal will use both male and post-menopausal female rats to investigate sex differences in hypertension-
induced HA dysfunction, and whether one sex is more susceptible to age- or hypertension-induced changes in
hippocampal neurovascular function. The outcome of these studies will provide an understanding of the
involvement of the hippocampal vasculature in memory decline associated with normal aging, and how this may
be accelerated during chronic hypertension and contribute to VCI.

Grant Number: 5R01NS127284-05
NIH Institute/Center: NIH
Principal Investigator: Abbie Chapman