Friday, April 4, 2025
4/4/2025
Aldosterone-Vascular Signaling on Cerebral Small Vessel Function - Project Summary Accumulating evidence has revealed cerebral small vessel dysfunction as a significant contributor to vascular cognitive impairment and dementia. Indeed, cerebral small vessel diseases (cSVD), an umbrella term referring to the structural and functional deterioration of cerebral small vessels, are responsible for nearly half of dementia cases. Notably, our compelling preliminary evidence suggests that excess plasma aldosterone (hyperaldosteronemia, HA) and subsequent blood pressure-independent activation of the mineralocorticoid receptors (MR)—the cognate receptor for aldosterone— deteriorates capillary-initiated vasodilatory responses in mice. Therefore, in response to the NIH Notice of Special Interest (NOT-HL-23-002) “Promoting research to understand vascular contributions to cognitive impairment and dementia (VCID)”, we propose to determine the mechanism(s) underlying cerebral small vessel dysfunction caused by HA-vascular MR signaling, focusing on the smallest vessels, capillaries, and small arterioles deep in the brain. Building on our preliminary data, we aim to test our overarching hypothesis that HA is an unappreciated risk factor for cSVD using HA model mice. Aim 1 will target brain endothelial cell (EC) MR signaling to protect against HA-induced deficits in functional hyperemia; an essential on-demand delivery mechanism of blood-borne nutrients and oxygen to metabolically active brain regions. Employing brain EC-specific MR knockout mice, we will test the hypothesis that HA deteriorates functional hyperemia through capillary EC-MR activation, independent of BP, systemic effects (e.g., cardiac remodeling, renal dysfunctions), and angiotensin II signaling. Aim 2 will probe the capillary EC-MR- mediated mechanisms by which HA impairs capillary-initiated vasodilatory signaling. We will target capillary EC strong inwardly rectifying potassium (Kir2.1) channels, which play a crucial role in functional hyperemia by sensing neuronal activity and, as a response, initiating vasodilatory-hyperpolarizing signaling. Capillary Kir2.1- mediated vasodilatory signaling will be examined by multi-faceted approaches ranging from the molecular level (e.g., patch-clamp electrophysiology, RNA sequencing) to ex vivo capillary-arteriole continuum preparations to in vivo CBF measurements. Aim 3 will examine the impact of HA-vascular MR signaling on small vessel function deep in the brain, specifically in the hippocampus and thalamus (critical regions for cognitive function). Kir2.1- mediated vasodilatory signaling, contractile properties in hippocampal and thalamic arterioles, and tissue perfusion will be assessed along with comparable studies using cortical vessels (Aims 1 and 2). Further, taking advantage of Innovative ultrafast ultrasensitive functional ultrasound imaging techniques, we will evaluate the impact of HA-vascular MR activation on in vivo hemodynamics deep in the brain. Thus, this project elucidating the mechanisms of small vessel dysfunction by HA-vascular MR activation will provide a wealth of valuable new information regarding the etiology of cSVD and VCID.
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