The role of VCAM1 in post-stroke cognitive impairment: Molecular mechanisms and therapeutic potential

Ischemic stroke constitutes a critical medical condition that can lead to post-stroke cognitive impairment (PSCI), yet the underlying molecular mechanisms remain incompletely understood. This study investigated the role of vascular cell adhesion molecule 1 (VCAM1) in cognitive dysfunction following ischemic stroke and evaluated its therapeutic potential. In a rat model of middle cerebral artery occlusion (MCAO), VCAM1 knockdown resulted in improved motor function, enhanced spatial memory, and reduced infarct size. Mechanistically, silencing VCAM1 was found to have mitigated blood-brain barrier (BBB) disruption by upregulating tight junction proteins such as Claudin-5, ZO-1, and Occludin. Additionally, it had suppressed cerebral microvascular hyperproliferation and decreased neuronal death via modulation of the Bax/Bcl-2 pathway. VCAM1 knockdown had also alleviated neuroinflammation by promoting microglial polarization toward the anti-inflammatory state (Arg1, CD206), while reducing the pro-inflammatory state (Iba-1, CD86). Concurrently, it had downregulated pro-inflammatory cytokines TNF-α and IL-1β and upregulated the anti-inflammatory cytokine IL-4. Transcriptome analysis identified VCAM1 as a key regulator within immune pathways, particularly enhancing PD-1/PD-L1 signaling, which was associated with cognitive recovery. Enrichment analyses demonstrated that VCAM1 knockdown alleviated cerebral ischemia-reperfusion injury in MCAO rats by modulating ion channel activity, calcium signaling pathways, and extracellular matrix interactions, while restoring dysregulated immune responses and cellular localization processes. Therefore, VCAM1 may be a promising therapeutic target for the treatment of PSCI.