Prostaglandin E2-EP2-NF-κB signaling in macrophages as a potential therapeutic target for intracranial aneurysms

Intracranial aneurysms are common but are generally untreated, and their rupture can lead to subarachnoid hemorrhage. Because of the poor prognosis associated with subarachnoid hemorrhage, preventing the progression of intracranial aneurysms is critically important. Intracranial aneurysms are caused by chronic inflammation of the arterial wall due to macrophage infiltration triggered by monocyte chemoattractant protein-1 (MCP-1), macrophage activation mediated by the transcription factor nuclear factor kappa B (NF-kappa B), and inflammatory signaling involving prostaglandin E-2 (PGE(2)) and prostaglandin E receptor subtype 2 (EP2). We correlated EP2 and cyclooxygenase-2 (COX-2) with macrophage infiltration in human intracranial aneurysm lesions. Monitoring the spatiotemporal pattern of NF-kappa B activation during intracranial aneurysm development in mice showed that NF-kappa B was first activated in macrophages in the adventitia and in endothelial cells and, subsequently, in the entire arterial wall. Mice with a macrophage-specific deletion of Ptger2 (which encodes EP2) or macrophage-specific expression of an I kappa B alpha mutant that restricts NF-kappa B activation had fewer intracranial aneurysms with reduced macrophage infiltration and NF-kappa B activation. In cultured cells, EP2 signaling cooperated with tumor necrosis factor-alpha (TNF-alpha) to activate NF-kappa B and synergistically induce the expression of proinflammatory genes, including Ptgs2 (encoding COX-2). EP2 signaling also stabilized Ccl2 (encoding MCP-1) by activating the RNA-stabilizing protein HuR. Rats administered an EP2 antagonist had reduced macrophage infiltration and intracranial aneurysm formation and progression. This signaling pathway in macrophages thus facilitates intracranial aneurysm development by amplifying inflammation in intracranial arteries. These results indicate that EP2 antagonists may therefore be a therapeutic alternative to surgery.