Abstract A064: Survivin-Mediated ECM Regulation and Cell Proliferation as a Therapeutic Strategy in Stroke

Introduction: Stroke remains the 5 th leading cause of death worldwide, yet its mechanisms and treatment options remain limited. Intracranial atherosclerotic disease, characterized by plaque formation in cerebral vessels, contributes to ischemic stroke, and both plaque stiffness and extracellular matrix (ECM) remodeling play critical roles in stroke pathology. Survivin ( BIRC5 ), a pro-proliferative&anti-apoptotic protein, is upregulated in pathological (stiff) vascular conditions like atherosclerosis, stroke, and hypertension, all of which are associated with increased stiffness. Survivin promotes plaque development, and is linked to poor cardiovascular outcomes. Although direct connections between survivin and stroke are limited, vascular stiffness remains a key risk factor. Methods: We analyzed a public RNA-seq dataset (GSE137482) of cerebral arteries from 18-month-old mice subjected to cerebral ischemia using the middle cerebral artery occlusion model ( Fig 1A ). Given that dysregulated vascular smooth muscle cells (VSMCs) are linked to vascular stiffening and survivin upregulation, both observed in ischemic stroke, we performed RNA-seq on human VSMCs with survivin knockdown cultured on a stiff hydrogel mimicking the mechanical properties of atherosclerosis or stroke-associated environments. Results: Analysis of the stroke dataset revealed enrichment of ECM-related terms in the Gene Ontology (GO) cellular component category, while biological processes were associated with signaling, development, and response to stimuli. Given that survivin modulates ECM synthesis and stroke-induced mice showed strong ECM enrichment, we analyzed matrisome gene expression and observed differential expression of collagens ( Fig 1B ), proteoglycans ( Fig 1C ), and ECM glycoproteins ( Fig 1D ) compared to controls. To examine survivin’s role, we compared the stroke dataset with the VSMC dataset ( Fig 2A ) and found that survivin inhibition dramatically altered both matrisome composition and proliferative pathways ( Fig 2B-D ), underscoring its therapeutic potential. Finally, Ingenuity Pathway Analysis (IPA) of the survivin knockdown dataset predicted mitigation of blood–brain barrier disruption and ischemic stroke, key processes in stroke pathology, through genes including APP, STAT3, and PLAT ( Fig 3A-B ). Conclusion: These findings suggest mechanistic links between survivin, vascular stiffness, and stroke, identifying potential targets for therapeutic strategies.