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

Abstract

Background: The microvasculature is a target organ for the early manifestations of cardiovascular disease. Therefore, a better understanding of the prostaglandin system and characterising the effects of mPGES-1 inhibition and concomitant reduction of PGE₂ in vascular beds are of interest.

Experimental approach: The effects of mPGES-1 inhibition on constriction and relaxation of resistance arteries (diameter: 100-400 μm) 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 unaffected by the COX-2 inhibitors NS-398 and Etoricoxib, or by the COX-1/COX-2 inhibitor Indomethacin tested in Non-ESKD controls. However, a significant increase of acetylcholine-induced dilatation was observed for mPGES-1 inhibition. 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. Blockade of PGI₂ signalling with an IP receptor antagonist did not restore the reduced adrenergic constriction, neither did blocking PGE₂ -EP4 or signalling through PPARγ. A biphasic effect was observed for PGE₂ , inducing dilatation at nanomolar and constriction at micromolar 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 are involved.

Keywords: ESKD; NSAIDs; PGE2; mPGES-1; microvasculature; resistance artery; wire myography.