Effects of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition on resistance artery tone in patients with end stage kidney disease

Background Inhibition of the microsomal prostaglandin (PG) E2 synthase (mPGES-1) introduces a promising anti-inflammatory treatment approach by specifically reducing PGE2 . The microvasculature is a central target organ for early manifestations of cardiovascular disease. Therefore, a better understanding of the prostaglandin system and characterising the effects of mPGES-1 inhibition in this vascular bed are of interest. Experimental approach The effects of mPGES-1 inhibition on constriction and relaxation of resistance arteries (O100-400μm) from patients with end stage kidney disease (ESKD) and controls (Non-ESKD) were studied using wire-myography in combination with immunological and mass-spectrometry based analyses. Key results Inhibition of mPGES-1 in arteries from ESKD patients and Non-ESKD controls significantly reduced adrenergic vasoconstriction, which was not affected by the COX-2 inhibitors NS-398 and Etoricoxib or the COX-1/COX-2 inhibitor Indomethacin, tested in Non-ESKD controls. Correspondingly, a significant increase of acetylcholine-induced dilatation was observed for mPGES-1 inhibition only. In IL-1β treated arteries, inhibition of mPGES-1 significantly reduced PGE2 levels while PGI2 levels remained unchanged. In contrast, COX-2 inhibition blocked the formation of both prostaglandins. Blockage of PGI2 signaling with an IP receptor antagonist did not restore the reduced constriction, neither did blocking of PGE2 -EP4 or signaling through PPARγ. A biphasic effect was observed for PGE2 , inducing dilatation at nmol and constriction at μmol concentrations. Immunohistochemistry demonstrated expression of mPGES-1, COX-1, PGIS, weak expression for COX-2 as well as receptor expression for PGE2 (EP1-4), thromboxane (TP) and PGI2 (IP) in ESKD and Non-ESKD. Conclusion Our study demonstrates vasodilating effects following mPGES-1 inhibition in human microvasculature and suggests that several pathways besides shunting to PGI2 may be involved.