P9 - AG Levkau /Keul Nathalie Schröder

Sphingosine-1-Phosphate (S1P) and its role in aortic aneurysms

S1P has numerous functions in the cardiovascular system in general, but its role in the pathogenesis of aneurysm formation in largely unknown. The underlying process involves proliferation and migration of vascular smooth muscle cells (VSMCs) along with vascular inflammation, and causally depends on the excessive activation of matrix metalloproteinases (MMPs), proteolytic enzymes that degrade the extracellular matrix (ECM) of the vessel. The most deleterious clinical consequence of MMP-dependent pathological remodeling of an artery is the formation of aortic aneurysms that progressively expand and ultimately rupture with extremely high mortality. Both our published and preliminary studies have revealed a causal interaction between S1P, S1P receptors and MMPs: we have shown that S1P3 protects, while pharmacological S1P elevation exacerbates pathological remodeling and aneurysm formation, and have identified S1P to inhibit TNFalpha-induced MMP-9 activation via S1P2. MMPs and S1P receptors are also known to be regulated in aortic aneurysms. Here, we will characterize the S1P receptors and the mechanisms by which they regulate aneurysm formation, progression and rupture in an angiotensin II-induced aneurysm model. We will use genetic and pharmacologic tools to influence individual S1P receptors and will employ them as strategies to inhibit and stabilize aneurysms. This may have immediate relevance for the clinic as there is no current consensus treatment of aneurysms besides extensive stenting and high-risk emergency surgery.