Vascular Endothelial Growth Factor and the Pathogenesis of Intracranial Aneurysms: A Systematic Review on the Missing Link in a Complex Pathway

Background Aneurysms are one of the most common and yet devastating cerebrovascular diseases after rupture. Despite several decades of scientific advancements including the expansion of the endovascular capabilities and noninvasive imaging modalities, no medical treatment exists to date. This failure is likely largely attributed to the complex and multifactorial nature of aneurysm pathophysiology. Recent research has increasingly implicated vascular endothelial growth factor (VEGF) in the development and rupture of intracranial aneurysms. Regarded as one of the most potent inducers of angiogenesis, it is a key factor in vascular wall maintenance, inflammation, and regulation of vascular permeability. Whether abnormal VEGF expression is directly related to aneurysm development or acting merely as an acute phase reactant remains uncertain. No review of the current-state-of-evidence on this topic exists yet.Methods and Results A systematic literature search was performed following PRISMA guidelines May 2024 that queried PubMed (1946-2024), Wiley Cochrane Library: Central Register of Controlled Trials (1898-2024), Thompson Reuters Web of Science: Citation Index (1900-2024), and Google Scholar (1946-2024). Inclusion criteria encompassed human and animal studies that investigated the relationship of intracranial aneurysm and VEGF. Several human and animal models revealed significantly elevated expression of VEGF in intracranial aneurysm tissue, along with greater levels in the cerebrospinal fluid and systemically. Overexpression has been shown to inhibit endothelial cell migration, proliferation, and induce cell apoptosis. Recently, genetic polymorphisms of VEGF have also been shown to significantly correlate with the presence of intracranial aneurysms, establishing the first genetic link between the two.Conclusions Despite lacking definitive evidence of a causal relationship, the wealth of supporting data substantiates VEGF as a promising topic for future investigation into aneurysm pathophysiology and as a potential therapeutic target.