Aging influences cerebrovascular myogenic reactivity and BK channel function in a sex-specific manner

Abstract

Aims The myogenic reactivity of the middle cerebral arteries (MCA) protects the brain by altering the diameter in response to changes in lumen pressure. Large conductance potassium (BK) channels are known to regulate the myogenic reactivity, yet, it is not clear how aging alters the myogenic reactivity via the BK channel in males and females. Thus, we hypothesize that age-associated changes in BK channel subunits modulate the myogenic reactivity in a sex-specific manner. Methods and results We used vascular reactivity, patch-clamp, and biochemical methods to measure myogenic reactivity, BK channel function, and expression, respectively in cerebral vessels of adult and aged male and female Sprague Dawley rats. Our results suggest that aging and ovariectomy (OVX) exaggerated the myogenic reactivity of MCA in females but attenuated it in males. Aging induced outward eutrophic remodelling in females but inward hypertrophic remodelling in males. Aging decreased total, Kv, BK channel currents, and spontaneous transient outward currents (STOC) in vascular smooth muscle cells isolated from females, but not in males. Aging increased BKα subunit mRNA and protein both in males and females. However, aging decreased BKβ1 subunit protein and mRNA in females only. In males, BKβ1 mRNA is increased, but protein is decreased. Iberiotoxin-induced MCA constriction is lower in aged females but higher in aged males. Activation of BKα (10 µM NS1619) and BKβ1 (10 µM S-Equol) subunits failed to increase STOCs and were unable to decrease the myogenic reactivity of MCA in aged female but not in aged male rats. OVX decreased, but chronic supplementation of oestradiol restored BK channel expression and function. Conclusion Overall our results suggest that aging or OVX-associated downregulation of the BKβ1 expression and function in females results in exaggerated myogenic reactivity of MCA. However, age-associated increase in BK channel function in males attenuated myogenic reactivity of MCA.

Sex differences in the structure and function of rat middle cerebral arteries

“…Calcium-activated K + channels are a negative feedback mechanism resulting in VSMCs membrane hyperpolarization and reduced vasoconstriction ( 8 , 53 ). A recent study indicated that VSMCs isolated from MCAs of adult female rats exhibited higher BK channel current densities compared with males leading to attenuated myogenic reactivity ( 61 ). In addition, a higher basal vascular tone would be expected to blunt subsequent myogenic responses ( 53 ).…”

“…Stroke survivors face long-term disability and cognitive deficits ( 37 ). Previous studies demonstrated that females have smaller MCA compared with males in humans ( 45 , 51 , 64 ) and in rats ( 61 ). The MCA in females has greater responses to hypercapnia, nitric oxide (NO), and flow-mediated vasodilation ( 31 , 47 , 54 , 56 ) and lower responses to angiotensin II (ANG II) as well as endothelin-1 (ET-1)-induced vasoconstriction ( 1 , 62 ).…”

BK Channel Dysfunction in Diabetic Coronary Artery: Role of the E3 Ubiquitin Ligases

“…However, it was also reported that NS1619 can also cause vasodilation by affecting multiple complementary pathways, including the stimulation of NO production, regulating other K + channels and L-type Ca 2+ channels (McCullough et al, 2014), i.e., NS1619 may have a nonspecific activation effect on BK channel activation. Besides that, more and more studies have reported that NS1619 is the activator of the BK-α subunit (Reed et al, 2019;Du et al, 2020). Therefore, the single experiment of vascular response to NS1619 is not enough to prove the effect of the BK channel.…”

Association of Age and Sex With Multi-Modal Cerebral Physiology in Adult Moderate/Severe Traumatic Brain Injury: A Narrative Overview and Future Avenues for Personalized Approaches

“…Finally, aside from estrogenic endothelial/myogenic and anti-inflammatory effects, there have been documented differences in potassium channel expression in males vs. females, with a direct link to estrogen levels ( Reed et al, 2020 ). In rats, large potassium channel beta-1 subunit (BK-B1) displays decreased expression in both males and female rats with removed ovaries.…”