Endothelial dysfunction is highlighted as an early marker of vascular abnormality preceding cerebral aneurysm formation, but the molecular events behind this transformation remain unclear. Inflammatory cytokines including interleukin-2 (IL-2) mediate vascular disease, but its role in cerebral aneurysm pathophysiology is unknown. Our preliminary data indicate that IL-2 is expressed in human cerebral aneurysm tissue and induces a phenotypic switch in endothelial cell (EC) function from the maintenance of vasomotor activity, to promotion of inflammation and matrix remodeling. We have also found that inhibition of the IL-2 target protein mTOR with rapamycin reduced aneurysm progression and rupture in a mouse cerebral aneurysm model. Collectively this preliminary data suggests a vital role of the IL-2/mTOR pathway in aneurysm progression. The objective of this grant is to characterize the role of IL-2 activated mTOR in EC dysfunction and aneurysm development and progression. The central hypothesis of this proposal is that IL-2/mTOR inhibition promotes repopulation of EC and decreases inflammation, which halts aneurysm progression and promotes vascular healing. In this proposal, we will determine the role of IL-2 activated mTOR in aneurysm formation, progression, and rupture and define the mechanisms by which IL-2/mTOR promotes EC dysfunction (Aim 1). We will treat experimental aneurysms with a novel stent delivering controlled release of the IL-2/mTOR inhibitor rapamycin to determine if IL-2/mTOR inhibition reverses EC dysfunction while decreasing inflammation (Aim 2). Finally, we will determine IL-2 expression, mTOR activation and EC dysfunction in human cerebral aneurysmal tissue and intra-aneurysmal blood and if rapamycin treatment prior to surgery reduces IL-2/mTOR signaling and EC dysfunction (Aim 3). The proposed research is innovative in that successful completion of this project will determine the events behind EC dysfunction which lead to aneurysm progression and will help develop novel minimally invasive therapeutic strategies for aneurysm obliteration.
Endothelial cell dysfunction occurs early during aneurysm formation and may contribute to the failure of aneurysm treatment. Upon conclusion of this study, we will have an understanding of the role of IL-2 activated mTOR in endothelial cell dysfunction leading to aneurysm formation, progression and rupture. The expected positive impact of this multi-disciplinary research is that by enhancing our understanding and prevention of endothelial cell dysfunction in aneurysm pathogenesis, clinicians will have novel medical therapies, imaging modalities, and minimally invasive endovascular devices for the successful treatment of cerebral aneurysms.
