Abstract 5312: Deletion of Microsomal Prostaglandin E2 Synthase-1 Modulates the Response to Vascular Injury in Mice
Microsomal (m) prostaglandin (PG) E2 synthase(S)-1 catalyzes the isomerization of the cyclooxygenase (COX) product, PGH2, into PGE2. Previous studies in mice suggest that targeting of mPGES-1 may less likely cause hypertension or thrombosis than COX-2 selective inhibitors in vivo. Indeed, deletion of mPGES-1 retards atherogenesis and angiotensin II induced aortic aneurysm formation. To address the role of mPGES-1 in the response to vascular injury, the effect of enzyme deletion on neointimal formation four weeks after wire injury of the femoral artery was assessed. mPGES-1 suppressed urinary excretion of the major metabolite of PGE2, while augmented that of prostacyclin (PGI2), a prostanoid that restrains vascular proliferation after the injury. Both maximal neointimal area and vascular stenosis were reduced significantly in mPGES-1 knock out mice compared to wild type controls (65.6±5.7 vs 37.7±5.1×103 pixel area and 70.5±13.4% vs 47.7±17.4%, respectively; in both cases, p < 0.01). Neointimal Tenascin C, a promoter of vascular smooth muscle cell (VSMC) proliferation is upregulated in response to vascular injury, and this was suppressed by mPGES-1 deletion. VSMCs isolated from mPGES-1 deficient mice exhibited delayed attachment and less coordinate migratory morphology when cultured on fibrillar type I collagen. Deletion of mPGES-1 impairs VSMC mobility and attenuates neointimal formation in response to vascular injury. Inhibition of mPGES-1 has therapeutic potential for the prevention of restenosis.
This research has received full or partial funding support from the American Heart Association, National Center.