Remote Ischemic Post-Conditioning Preserves the Neurovascular Unit by Brain-Derived Gas6 That Drives Monocyte-Derived Macrophage Reprogramming via Axl and Vimentin after SAH.

Subarachnoid hemorrhage (SAH) causes long-term cognitive dysfunction due to early brain injury, but effective therapies are limited. Remote ischemic post-conditioning (RIPostC) confers neuroprotection, but its mechanisms remain incompletely understood. Here we show that RIPostC preserves the neurovascular unit by modulating monocyte-derived macrophages (MDMs) via the Gas6/Axl/Vimentin axis. In 405 SAH patients, elevated cerebrospinal fluid leukocyte counts correlate positively with Hunt-Hess and 3-month mRS scores. In a rat SAH model, RIPostC suppresses periventricular CCR2+ cell infiltration, reduces MDMs, shifts their polarization from M1-like to M2-like, preserves blood-brain barrier integrity, and improves cognitive function. Mechanistically, RIPostC downregulates Vimentin. However, the Vimentin inhibitor Withaferin A mimics anti-infiltration but does not promote M2-like polarization. RIPostC upregulates neuronal Gas6, which engages MDM Axl. Besides, Gas6 knockdown abolishes RIPostC's protective effects. Additionally, RIPostC selectively expands a reparative Stab1+Clec10a+ MDM subset. In human THP-1 cells, recombinant Gas6 suppresses Vimentin and induces M2-like polarization via Axl, and the Axl inhibitor R428 blocks this effect. Thus, RIPostC enhances neuronal Gas6 to activate MDM Axl and downregulate Vimentin, limiting infiltration and driving reparative polarization, which preserves neurovascular unit integrity and improves cognition after SAH.