Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4505, USA.
Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, 600 Moye Blvd, Greenville, NC 27834-4300, USA.
Cardiovasc Res. 2020 Jun 1;116(7):1372-1385. doi: 10.1093/cvr/cvz314.
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.
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.
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.
大脑中动脉（MCA）的肌源性反应通过改变管腔压力下的直径来保护大脑。已知大电导钾（BK）通道调节肌源性反应，但尚不清楚衰老如何通过雄性和雌性中的 BK 通道改变肌源性反应。因此，我们假设与年龄相关的 BK 通道亚基变化以性别特异性方式调节肌源性反应。
我们使用血管反应性、膜片钳和生化方法分别测量成年和老年雄性和雌性 Sprague Dawley 大鼠脑血管的肌源性反应、BK 通道功能和表达。我们的结果表明，衰老和卵巢切除术（OVX）使雌性 MCA 的肌源性反应过度，但在雄性中减弱。衰老导致雌性的外向性营养性重塑，而雄性的内向性肥大性重塑。衰老减少了雌性血管平滑肌细胞中的总、Kv、BK 通道电流和自发性瞬时外向电流（STOC），但对雄性没有影响。衰老增加了雄性和雌性的 BKα亚基 mRNA 和蛋白。然而，衰老仅降低了雌性中的 BKβ1 亚基蛋白和 mRNA。在雄性中，BKβ1 mRNA 增加，但蛋白减少。IBTX 诱导的 MCA 收缩在老年雌性中较低，但在老年雄性中较高。BKα（10 μM NS1619）和 BKβ1（10 μM S-Equol）亚基的激活未能增加 STOC，并且不能降低老年雌性而非老年雄性大鼠 MCA 的肌源性反应。OVX 降低，但慢性雌激素补充恢复了 BK 通道表达和功能。
总体而言，我们的结果表明，衰老或 OVX 相关的 BKβ1 表达和功能下调导致雌性 MCA 的肌源性反应过度。然而，雄性中与年龄相关的 BK 通道功能增加减弱了 MCA 的肌源性反应。
