Structural Weakness: Collagen Alterations in Cerebral Aneurysm Development

Background/Objectives: Aneurysms develop secondary to progressive weakening of arterial walls and remain a major cause of morbidity and mortality worldwide. Collagen, particularly fibrillar types I and III, is the primary tensile load-bearing component of arteries, yet its specific role in aneurysm formation, progression, and rupture is incompletely defined. This narrative review synthesizes current evidence on collagen structure, regulation, and degradation in aneurysm pathophysiology, highlighting cerebral aneurysms within the broader context of aneurysms as a whole. Methods: Searches of PubMed, MEDLINE, Embase, and Google Scholar were performed to identify all English-language studies published prior to January 2026. Search terms included “cerebral aneurysm”, “collagen”, “extracellular matrix”, “vascular remodeling”, and “aneurysm rupture”. Included studies evaluated collagen structure or content, extracellular matrix remodeling, matrix metalloproteinases, or biomechanical properties of the aneurysm wall in experimental or human models. Results: The literature search identified 348 records, of which 87 studies published between 1999 and 2025 met the inclusion criteria and were synthesized in this review. Collagen types I and III form the primary tensile scaffold of intracranial arteries, while basement membrane and regulatory collagens (e.g., types IV, V, and VI) modulate fibril organization, endothelial stability, and mechanical homeostasis. Research demonstrates that endothelial dysfunction, nitric oxide dysregulation, oxidative stress, and matrix metalloproteinase activation are key pathways driving collagen fragmentation and degradation. Genetic and epigenetic disturbances in collagen and related extracellular matrix pathways further increase aneurysm susceptibility. Conclusions: Collagen dysregulation appears to be a final common pathway through which hemodynamic, inflammatory, hormonal, and genetic insults converge to weaken intracranial arterial walls. However, existing evidence is dominated by animal and aortic models, and in vivo tools, such as Magnetic Resonance Imaging with collagen-sensitive sequences and Positron Emission Tomography Tracers, to quantify collagen integrity in cerebral aneurysms are lacking. Future efforts should prioritize human-focused studies, advanced collagen-sensitive imaging, biomarker development, and targeted strategies to preserve or restore collagen structure as potential means to improve aneurysm risk stratification, prevention, and treatment.