Estrogen Enhances SK Channel Activity to Limit Hippocampal Arteriole Constriction

Abstract

Background: Arteries and arterioles exhibit myogenic tone, a partially constricted state that allows for further constriction or dilation. The vascular endothelium provides tonic vasodilatory influence by controlling adjacent smooth muscle cell contractility. Studies on surface cerebral arteries show that estrogen lowers myogenic tone in female mice by enhancing NO release; however, it is unclear whether this extends to intracerebral microcirculation. The incomplete understanding of sex differences and aging's impact highlights the need to investigate sexual dimorphism within the parenchymal microcirculation. We hypothesized that sex hormone regulation of myogenic tone extends to the microcirculation and characterized this in isolated arterioles from the hippocampus, a predominant cognitive brain region vulnerable to vascular injuries.

Methods: We measured arteriolar diameter both in vivo, through an acute cranial window and 2-photon microscopy, and ex vivo, using advanced pressure myography. Pharmacological interrogation was utilized to probe endothelial-dependent vasodilation, and ovariectomy was performed on female mice to probe the effect of estrogen. We used immunohistochemistry and electrophysiology to measure small-conductance Ca²⁺-sensitive K⁺ (SK) channel expression and activity, respectively.

Results: We observed lower myogenic responses in arterioles from female compared with male mice and found that myogenic tone in ovariectomized female mice matched that of males. Interestingly, NOS (nitric oxide synthase) inhibition only partially abolished the difference in tone. We identified that the dominant remnant difference was mediated by higher activity and expression of SK channels. Notably, both NO and SK channels enhanced signaling appeared governed by circulating estrogen. We further investigated whether aging diminished this sexual dimorphism and found that myogenic tone and SK channel activity differences persisted, while NO-related differences were reduced.

Conclusions: These data highlight a canonical shift from NOS to SK channel activity in estrogen-influenced intracerebral blood flow regulation, which persists in aged mice.

Keywords: arterioles; blood pressure; cardiovascular diseases; endothelium; estrogens; hippocampus; potassium channels.