NF-kB activation in intracranial aneurysm formation and early growth.

In recent decades, understanding the molecular mechanisms leading to cerebral aneurysm development has been limited. Advances in molecular biology now suggest a plausible explanation, rooted in a chronically unbalanced high hemodynamic environment. Molecular evidence from human and animal intracranial aneurysm specimens indicates a common pathway, where hemodynamic stresses on the endothelium play a pivotal role. This results in endothelial dysfunction, initiating a cascade of inflammatory vessel wall remodeling and degenerative changes. Notably, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activated in response to turbulent flow, upregulates inflammation-related genes, contributing to aneurysm formation. Further elucidation of NF-κB's role in hemodynamic stress-induced upregulation and its impact on structural remodeling holds potential for understanding and addressing cerebral aneurysm formation and progression.NF-κB is essential for initiating inflammatory responses in endothelial cells, and its activation is influenced by fluid flow variations. Laminar WSS leads to a decline in signaling to NF-κB, while disrupted WSS increases nuclear localization. NF-κB expression is upregulated in zones susceptible to atherogenesis, but the full activation of NF-κB depends on supplementary components, such as inflammatory cytokines. NF-κB is activated in various cell types, including smooth muscle cells, macrophages, and endothelial cells, and plays a role in intracranial aneurysmal formation. Research shows that human atherosclerotic lesions include activated NF-κB, and mouse studies show a correlation between regions prone to aneurysmal formation and elevated NF-κB components. NF-κB plays a crucial role in intracranial aneurysmal formation by regulating enzymes that generate inflammatory lipid mediators. It also regulates monocyte chemoattractant protein-1, a chemokine essential for drawing monocytes during atherosclerotic lesion formation. NF-κB also regulates adhesion molecules in response to inflammation signals, which are correlated with the progression of aneurysmal formation in mouse models. Tumor necrosis factor alpha has been implicated in the activation of NF-κB, correlating with the development of cerebral aneurysms. TNF-alpha, a proinflammatory cytokine, is associated with inflammation and apoptosis in vascular diseases such as atherosclerosis and aneurysms. It mediates endothelial dysfunction characterized by increasing inflammatory cell recruitment across the vessel endothelium. TNF-alpha has been found to be upregulated in unruptured cerebral aneurysms compared with ruptured cerebral aneurysms, suggesting that TNF-alpha initiates early formation and growth of cerebral aneurysms but not sustained development leading to rupture. The prostaglandin E2 pathway has also been implicated in the genesis of cerebral aneurysms through the activation of NF-κB. PGE2, derived from arachidonic acid, acts on prostaglandin E receptor subtype 2, the factor capable of activating downstream NF-κB in the arterial wall. Blockade of both EP2 and COX-2 inhibition inhibits NF-κB activation and subsequent intracranial aneurysmal formation. In conclusion, wall shear stress can induce COX-2 and EP2 expression in cultured endothelial cells, potentially leading to the formation and maintenance of a chronic inflammatory process within the arterial wall, eventually succumbing to intracranial aneurysm formation. Endothelial dysfunction is a cornerstone pathognomic event in the initiation of cerebral aneurysm development. It refers to the upregulation of specific proinflammatory genes by the vascular endothelium through the transcription factor NF-κB and is responsible for the induction of adhesion and matrix remodeling molecules such as VCAM and MCP. It serves as a pathological link connecting the influence of abnormal wall shear stress and the attendant downstream inflammatory reaction in the arterial wall. The infiltration of inflammatory cells into the vessel wall is a pivotal hallmark in the genesis of nascent cerebral aneurysms. Leukocytes initially participate in the acute inflammatory process, secreting proteases that degrade the extracellular matrix, leading to vessel wall remodeling and aneurysm formation. Later, macrophages become the predominant inflammatory cell in the intracranial aneurysm wall contributing to aneurysmal development through the synthesis and release of proinflammatory cytokines and specific proteases such as matrix metalloproteinases that impair the integrity of the extracellular matrix. Inhibition of tissue inhibitors of matrix metalloproteinase facilitates cerebral aneurysm development by upregulating MMP activity. Inhibiting NF-κB P50 expression and activation decreases the likelihood of IA formation, while higher NF-κB activation associates with an increase in IA formation. Treatments that prevent the development, growth, and rupture of IAs hinder the mRNA expression, protein levels, and/or phosphorylation of NF-κB P65, indicating the significant role of NF-κB stimulation in the development and rupture of IAs. Inhibiting or suppressing NF-κB activation in specific cell types has yielded intriguing outcomes, such as reducing the occurrence of IA formation in macrophages but not in endothelial cells. Smooth muscle cells (SMCs) may also play a role in IA development and progression, suggesting that a single cellular source of NF-κB activation appears less likely in IA development and progression. [ABSTRACT FROM AUTHOR]