Age‐Associated Changes in Cerebrovascular Function and BK Channel Function are Sex‐Specific

Abstract

Large conductance potassium (BK) channels are known to regulate the myogenic reactivity, yet, it is not clear if 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. We used vascular reactivity, patch‐clamp, and biochemical methods to measure the myogenic reactivity, BK channel function, and expression, respectively, in cerebral vessels of adult and aged male and female Sprague Dawley rats. The results suggest that aging and ovariectomy (OVX) exaggerated the myogenic reactivity of middle cerebral arteries (MCA) in females but attenuated it in males. Aging induced outward eutrophic remodeling in females but inward hypertrophic remodeling 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 content both in males and females. However, aging decreased BKβ1 subunit protein and mRNA levels 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. OVX decreased, but chronic supplementation of estradiol (OVX+17βE rats) restored BK channel expression and function. BKβ1 mRNA is decreased in cerebral vessels of OVX rats that is consistent with decreased protein content. However, supplementation with 17βE did not increase mRNA, but protein is not decreased suggesting that post‐translational mechanisms contribute to the preservation of the protein. Overall the results suggest that aging and OVX‐associated downregulation of the BKβ1 expression and function in females exaggerates the myogenic reactivity of MCA. However, age‐associated increase in BK channel function in males attenuates the myogenic reactivity of MCA. Support or Funding Information This work was supported by, in part, by a grant from the Intramural Research Support Program from UMMC and AHA Scientist Development Grant 13SDG14000006 (M. R. Pabbidi).