Microvascular changes that stagger the mind

Abstract

Hypertension is a leading cause of cognitive impairment and dementias. Such loss of brain health has a vascular component, but the mechanisms involved are poorly defined. In this issue of the JCI, Koide et al. provide evidence that end-organ effects of hypertension on capillary endothelium and inward-rectifier K+ channels (Kir2.1) impair integrated propagation of electrical signals and vasodilation upstream, resulting in reduced neurovascular coupling (NVC) despite neural activation. NVC was partly restored by amlodipine, but not losartan. Moreover, NVC was improved by eplerenone in the presence of losartan, suggesting a role for aldosterone. These findings support the concept that endothelial cells and Kir2.1 are potential therapeutic targets to prevent or reverse the loss of NVC and the vascular component of cognitive deficits that occur with increased frequency during hypertension.

Figure 1. Impact of hypertension on neurovascular coupling.

(A) Hypertension impacts major adaptive features that contribute to regulation of CBF. Loss of these mechanisms results in reductions in NVC, CBF, development and progression of cognitive deficits, and eventually dementias. (B) In normotensive individuals, activated neurons release K⁺. Extracellular K⁺ activates Kir2.1 channels on capillary endothelial cells to release K⁺, resulting in membrane hyperpolarization that spreads upstream from endothelial cells to adjacent endothelial cells as well as to vascular muscle cells. Hyperpolarization of vascular muscle produces vasodilation. CBF, cerebral blood flow; RAAS, renin-angiotensin-aldosterone system; TA, transition arteriole; NVC, neurovascular coupling.