Date of Award


Document Type


Degree Name

Master of Science (MS)



First Advisor

Masayo Koide


Aldosterone, a steroid hormone, plays an important role in blood pressure homeostasis and the maintenance of plasma electrolyte levels by activating the mineralocorticoid receptor (MR) in renal distal tubule and collecting duct epithelial cells. Recent studies revealed that MRs are also expressed in other tissues, including cardiac myocytes, vascular smooth muscle cells, and vascular endothelial cells (EC), and that elevated plasma aldosterone, termed hyperaldosteronemia (HA), has deleterious effects on the cardiovascular system. However, little is known about the impact of HA on cerebral blood flow (CBF) regulation and brain health. HA is present in 10-30% of hypertensive patients, with unrecognized and asymptomatic HA estimated to occur in > 10% of normotensive individuals. Regardless of blood pressure, HA adversely impacts cardio- and cerebro-vascular systems. We have previously shown that, despite comparable blood pressure, animals with HA exhibit impaired functional hyperemia, the physiological process that supports the on-demand delivery of blood to regions of heightened neuronal activity. This local CBF increase in the active region(s) of the brain is underpinned by strong inward rectifier K+ (Kir 2.1) channels in capillary endothelial cells (cECs). Capillary Kir2.1 channels sense increased neuronal activity and subsequent Kir2.1 channel activation initiates vasodilatory signaling (i.e., hyperpolarization), leading to a local CBF increase at the site where the signal is initiated. Therefore, this study aimed to elucidate the molecular mechanism underlying HA-induced functional hyperemia deficits by measuring Kir2.1 channel currents in cECs. Further, employing EC-specific MR-knockout (EC-MR-KO) mice, we examined the contribution of MR on the adverse impact of HA on CBF regulation. First, we characterized our newly developed HA model mice, which received exogenous aldosterone (or vehicle) through a subcutaneously implanted osmotic pump. Plasma aldosterone levels, blood electrolyte concentrations, and systemic blood pressure were measured. Next, using the conventional whole-cell configuration of the patch-clamp technique, Kir2.1 channel currents were measured in freshly isolated cECs obtained from wildtype (WT) or EC-MR-KO mice treated with aldosterone or vehicle as Ba2+-sensitive inward currents. Plasma aldosterone levels were significantly increased in aldosterone-treated animals without altering systemic blood pressure. Plasma K+ levels were slightly decreased in aldosterone-treated WT and EC-MR-KO mice, while other plasma electrolytes remained unchanged. Kir2.1 channel currents were significantly decreased in cECs obtained from aldosterone-treated WT mice compared to vehicle-treated WT mice. Notably, capillary Kir2.1 channel currents in aldosterone-treated EC-MR-KO mice were comparable to that in vehicle-treated WT and vehicle-treated EC-MR-KO mice. These data suggest aldosterone diminishes capillary Kir2.1 channel currents via EC-MR signaling, leading to functional hyperemia deficits. As functional hyperemia is crucial to maintain brain functions such as cognition, targeting EC-MR signaling and the capillary Kir2.1 channel may have therapeutic potential to prevent HA-induced functional hyperemia deficits and cognitive decline.



Number of Pages

59 p.

Available for download on Friday, April 17, 2026