Friday, April 26, 2024
4/26/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
