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Basic Molecular and Genetic Pathways Underlying Intracranial Aneurysm Formation in the Era of Molecular and Targeted Therapies: A 10-Year Review

Year: 2026

Type: article

Abstract: Introduction: Intracranial aneurysms (IAs) are focal dilatations of cerebral arteries that carry a significant risk of rupture and subarachnoid hemorrhage (aSAH). Advances in basic science have improved understanding of vascular wall biology, hemodynamic stress, inflammation, and genetic contribution to aneurysm rupture. Rapid progress in neurovascular therapeutics highlights the need to evaluate emerging molecular and pharmacologic strategies targeting IAs. Methodology: This narrative review synthesizes evidence from 2015 to 2025 on the cellular, molecular, and biomechanical mechanisms underlying IA pathophysiology. A structured search of PubMed, Scopus, and Embase identified studies examining molecular pathways, genetic determinants, and therapeutic approaches. Discussion: Aneurysm initiation involves endothelial responses to abnormal shear stress, activating NF-κB, MAPK, and calcium-dependent pathways that promote inflammation, smooth-muscle cell apoptosis, and extracellular matrix degradation. Pharmacologic candidates including MCP-1 antagonists, PPARγ agonists, and IL-6/STAT3 inhibitors reduce inflammatory remodeling, while doxycycline and cathepsin inhibitors preserve matrix integrity. Emerging strategies like microRNA modulation, tyrosine-kinase inhibition, and gene-based delivery offer potential for localized, durable stabilization with minimal systemic toxicity. Conclusions: Integrating surgical and biologic therapies may shift IA management from reactive repair to rupture prevention.

Source: Journal of Vascular Diseases

DOI: 10.3390/jvd5020015

Authors: Denise Baloi, Henry Freeman, Moneebah Ashraf, Michael Karsy, Brandon Lucke-Wold, Mehrdad Pahlevani