← Back to Previous Page

 

S113: BASIC MOLECULAR AND GENETIC PATHWAYS UNDERLYING INTRACRANIAL ANEURYSM FORMATION AND RUPTURE IN THE ERA OF MOLECULAR AND TARGETED THERAPIES, A 10-YEAR REVIEW.
Denise Baloi¹; Henry Freeman²; Moneebah Ashraf³; Michael Karsy, MD⁴; Brandon Lucke-Wold, MD, PhD⁵; Mehrdad Pahlevani, MD⁶; ¹Michigan State University College of Human Medicine; ²Michigan State University College of Osteopathic Medicine; ³Central Michigan University College of Medicine; ⁴Department of Neurosurgery, University of Michigan; ⁵Department of Neurosurgery, University of Florida; ⁶Department of Neurosurgery, Jamaica Hospital Medical Center

Introduction: Intracranial aneurysms (IAs) are focal dilatations of cerebral arteries that, while often asymptomatic, carry the devastating risk of rupture leading to aneurysmal subarachnoid hemorrhage (aSAH). Recent advances in basic and translational science have expanded understanding of the interplay between vascular wall biology, hemodynamic stress, inflammatory mediators, and genetic predispositions in aneurysm initiation, progression, and rupture. Rapidly growing neuro vascular technologies and therapies emphasize the need for extensive and comprehensive assessment of modern pharmacological micromolecular therapies targeting intracranial aneurysm.

Methodology: This narrative review synthesizes current evidence (2015-2025) on the cellular, molecular, and biomechanical drivers of IA pathophysiology and highlights emerging opportunities for biologically targeted therapies. A comprehensive search of PubMed, Scopus, and Embase was performed to identify studies published in the last decade that evaluated the molecular biology, genetic components and evolving micro molecular target therapies of intracranial aneurysm.

Discussion: Aneurysm development begins with disruption of the internal elastic lamina and extracellular matrix remodeling, shifting the vessel’s load-bearing capacity and predisposing it to structural failure. Endothelial mechanical sensing of abnormal wall shear stress activates NF-κB, MAPK, and calcium-dependent cascades, leading to proinflammatory cytokine release, endothelial dysfunction, and smooth muscle cell (SMC) apoptosis. Subsequent recruitment of macrophages, neutrophils, lymphocytes, and mast cells amplifies vascular inflammation through secretion of IL-1, IL-6, TNF-α, prostaglandins, and matrix metalloproteinases (MMPs), further degrading the aneurysm wall.

Experimental approaches targeting macrophage recruitment (MCP-1 blockade, PPARγ agonists), inflammatory cascades (TNF-α inhibitors, IL-6/STAT3 antagonists), and matrix degradation (doxycycline, cathepsin inhibitors) show promise in reducing aneurysm growth and rupture in preclinical models. Gene and pathway-directed therapies, including tyrosine kinase inhibitors for PDGFRB-driven remodeling and microRNA-based modulation of SMC phenotype, represent emerging translational strategies. Advances in local drug and gene delivery platforms, such as hydrogel embolics and viral vectors, may enable site-specific, durable biologic stabilization of aneurysm walls.

Conclusion: In summary, intracranial aneurysms arise from the convergence of vascular wall remodeling, hemodynamic stress, inflammatory cell infiltration, and genetic predisposition. Ongoing translational research continues to refine mechanistic insights and identify novel molecular targets. Future therapies integrating surgical, pharmacologic, and biologic strategies hold potential to shift management of IAs from reactive interventions toward proactive stabilization and prevention of rupture.

 

← Back to Previous Page