Female sex protects cerebral arteries from mitochondrial membrane potential depolarization and cell death induced by reactive oxygen species
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Stroke, Alzheimer's disease, and traumatic brain injury exacerbate the production of reactive oxygen species (ROS), leading to apoptosis in cerebral arteries. Notably, females exhibit greater resilience to vascular damage compared to males. Mitochondrial membrane potential ([delta][psi]m) depolarization is a pivotal event in apoptosis. However, under significant depolarization, ATP synthase can reverse direction, acting as a proton pump to mitigate [delta][psi]m depolarization. Additionally, alterations in the electron transport chain function may regulate [delta][psi]m. Furthermore, plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor present in cerebral arteries, can promote cellular resilience, although its effects on mitochondrial function have not been defined. We hypothesize that during acute oxidative stress induced by exposure to H2O2, female protection of posterior cerebral arteries (PCAs) is facilitated by enhanced reverse ATP synthase activity, augmented mitochondrial electron transport function, and PAI-1 signaling. PCAs (80 [mu]m diameter) from male and female mice (age: 4-6 months) were isolated, cannulated, and pressurized to 90 cm H2O2 at 37 degreesC. Cell death was quantified with Hoechst 33342 (1 [mu]M, labels all nuclei) and propidium iodide (2 [mu]M, labels dead nuclei), and mitochondrial membrane potential ([delta][psi]m) at rest was evaluated by JC-1 and during depolarization with H2O2 with tetramethylrhodamine methyl ester (TMRM, 10 nM). H2O2 exposure (50 min) led to significantly (P<0.05) greater smooth muscle cell death in males compared to females (30 [plus or minus] 7.4 percent vs. [approx] 7 [plus or minus] 3 percent; n=8); there was a similar trend for endothelial cell death. The ATP synthase inhibitor oligomycin (2 [mu]M) greatly augmented apoptosis in PCAs from both males and females to [approx]80 percent and eliminated differences between sexes. Consistently, H2O2 evoked a more robust depolarization of [delta][psi]m in males vs. females and oligomycin enhanced [delta][psi]m depolarization to H2O2. Oxygen consumption rate (OCR) in females was significantly higher at baseline and when exposed to H2O2, while glycolysis was not altered by exposure to H2O2. In females, PAI-1 signaling contributes to resilience against acute oxidative stress damage, whereas males exhibit greater protection in the absence of PAI-1. We conclude that cerebral vessels from female mice possess greater resilience to H2O2 -induced apoptosis than males by limiting depolarization of [delta][psi]m and though sex differences in PAI-1 signaling.
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M.S.