Berberine suppresses mechanical stretch-induced apoptosis and proliferation in vascular smooth muscle cells via ROS/PDI/Drp1 signaling pathway.

Background: Vascular smooth muscle cells (VSMCs) exhibit heterogeneous responses to mechanical stretch stress (SS), with some undergoing apoptosis and others proliferating. The mechanisms underlying this differential fate decision remain unclear. Objective: This study investigated whether SS-induced heterogeneity in F-actin expression dictates distinct mitochondrial reactive oxygen species (ROS) responses, leading to different VSMC fates, and evaluated the therapeutic potential of the berberine (BBR). Methods: VSMCs were subjected to SS. F-actin heterogeneity was characterized, and mitochondrial ROS (mtROS), proliferation, and apoptosis were assessed. The involvement of the PKCα/PDI/Drp1 signaling axis was examined using pharmacological inhibitors and BBR. Results: SS induced heterogeneous mtROS production in VSMCs with varying F-actin levels. This differential ROS signaling concurrently activated the pro-proliferative mTOR/p70 pathway and the pro-apoptotic caspase-9/3 cascade via the PKCα/PDI/Drp1 axis. Importantly, BBR treatment effectively attenuated both SS-induced proliferation and apoptosis by suppressing PKCα activation and subsequent mitochondrial signaling. Conclusion: Our findings reveal that F-actin heterogeneity determines VSMC fate under SS by driving distinct mitochondrial ROS responses. BBR, by counteracting these ROS-dependent pathways, emerges as a promising therapeutic strategy for managing stretch-related vascular pathologies, such as hypertension-induced atherosclerosis.