Aging Cell · Feb 21, 2024

Advanced age and female sex protect cerebral arteries from mitochondrial depolarization and apoptosis during acute oxidative stress

By Norton CE, Shaw RL, Safa et al.

Aging increases reactive oxygen species (ROS) which can impair vascular function and contribute to brain injury. However, aging can also promote resilience to acute oxidative stress. Therefore, we tested the hypothesis that advanced age protects smooth muscle cells (SMCs) and endothelial cells (ECs) of posterior cerebral arteries (PCAs; diameter, ∼80 μm) during exposure to H₂O₂. PCAs from young (4-6 months) and old (20-26 months) male and female C57BL/6 mice were isolated and pressurized (~70 mm Hg) to evaluate cell death, mitochondrial membrane potential (ΔΨm), ROS production, and [Ca²⁺]i in response to H₂O₂ (200 μM, 50 min). SMC death and ΔΨm depolarization were greater in PCAs from males vs. females. Aging increased ROS in PCAs from both sexes but increased SMC resilience to death only in males. Inhibiting TRPV4 channels with HC-067047 (1 μM) or Src kinases with SU6656 (10 μM) reduced Ca²⁺ entry and SMC death to H₂O₂ most effectively in PCAs from young males. Activating TRPV4 channels with GSK1016790A (50 nM) evoked greater Ca²⁺ influx in SMCs and ECs of PCAs from young vs. old mice but did not induce cell death. However, when combined with H₂O₂, TRPV4 activation exacerbated EC death. Activating Src kinases with spermidine (100 μM) increased Ca²⁺ influx in PCAs from males vs. females with minimal cell death. We conclude that in males, chronic oxidative stress during aging increases the resilience of cerebral arteries, which contrasts with inherent protection in females. Findings implicate TRP channels and Src kinases as targets to limit vascular damage to acute oxidative injury.

doi.org/10.1111/acel.14110Open accessPubMed 38380477Mechanisms