Estrogen Enhances SK Channel Activity to Limit Hippocampal Arteriole Constriction

Area of Science:

• Neurovascular function
• Cerebral microcirculation
• Vascular smooth muscle physiology

Background:

• Arteries and arterioles possess myogenic tone, a state of partial constriction influencing blood flow.
• Estrogen is known to lower myogenic tone in surface cerebral arteries by enhancing nitric oxide (NO) release.
• The impact of sex hormones and aging on intracerebral microcirculation's myogenic tone remains poorly understood.

Purpose of the Study:

• To investigate sex differences in myogenic tone within the hippocampus's microcirculation.
• To determine if estrogen's regulation of myogenic tone extends to intracerebral arterioles.
• To characterize the roles of NO and small-conductance Ca2+-sensitive K+ (SK) channels in sex-based differences in arteriolar tone.

Main Methods:

• In vivo and ex vivo measurements of arteriolar diameter using 2-photon microscopy and pressure myography.
• Pharmacological inhibition of nitric oxide synthase (NOS) and ovariectomy in female mice.
• Immunohistochemistry and electrophysiology to assess SK channel expression and activity.

Main Results:

• Female mice exhibited lower myogenic responses in arterioles compared to males.
• Ovariectomy normalized myogenic tone in females to levels seen in males, indicating estrogen's role.
• While NO contributed, higher SK channel activity and expression were the primary drivers of the remaining sex difference in tone.
• These NO and SK channel differences were estrogen-dependent and persisted in aged mice, though NO-related differences diminished.

Conclusions:

• Estrogen influences intracerebral blood flow regulation by modulating myogenic tone in arterioles.
• A key finding is a shift from nitric oxide synthase (NOS) to SK channel activity in estrogen-mediated regulation.
• This NOS-to-SK channel shift is maintained in aged mice, highlighting its significance in long-term neurovascular health.