Introduction: Cerebral Aneurysm rupture results in significant morbidity and mortality. TNF-a has been associated with cerebral aneurysms, but potential mechanisms have not been established, and its role in phenotypic modulation is unknown. Therapy targeting TNF-a may represent a novel treatment strategy for cerebral aneurysms.
Methods: Cultured cerebral VSMC were incubated with increasing concentrations of TNF-a (5 ng/ml and 50 ng/ml) for 24 hours. Cerebral aneurysm induction surgery was performed in rats. Animal were euthanized at 4 weeks for qPCR and immunohistochemical analysis of the circle of Willis. Animals undergoing aneurysm induction and Infliximab (5mg/kg) treatment were compared to animals undergoing aneurysm induction alone and untreated controls.
Results: In vitro experiments demonstrated suppression of differentiation markers and induction of pro-inflammatory genes. In vivo, TNF-a mRNA and protein expression was significantly elevated following aneurysm induction compared to untreated controls. Expression of inflammatory markers including chemokines (MCP1 and VCAM1), transcription factors (NF-?B, KLF4), matrix remodeling proteins (MMP-2 & 3), IL-1ß and iNOS was also increased. Furthermore, aneurysm induction resulted in phenotypic modulation by decreasing expression of SMC differentiation marker gene SM-a-Actin. Treatment with Infliximab significantly suppressed TNF-a activity, inhibited expression of inflammatory markers, and decreased the number of CD68+ cells during aneurysm formation. Infliximab also reversed phenotypic modulation in vascular SMC following aneurysm induction.
Conclusions: ??F-a plays a pivotal role in SMC phenotypic modulation with induction of pro-inflammatory genes and inhibition of SMC differentiation marker genes both in cultured cerebral vascular SMC and in vivo following cerebral aneurysm induction. Infliximab promotes anti-inflammatory effects in cerebral vessels by inhibiting TNF-a and suppressing a pro-inflammatory cascade, which has important implications for the mechanisms behind intracranial aneurysm formation and potential therapeutic options.
Patient Care: Current understanding of aneurysm biology is inadequate. Better understanding the underlying pathology will help us develop non or minimally invasive treatment options for patients.
Learning Objectives: By the conclusion of this session, participants should be able to:
1) the role of cerebral vascular smooth muscle (VSMC) phenotypic modulation in aneurysm formation and progression
2) the role of tumor necrosis factor-alpha in inducing phenotypic modulation in VSMC and inflammatory up-regulation
3) role of Infliximab (a specific TNFa inhibitor) in suppressing inflammatory up-regulation induced by TNFa in vivo