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

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-1ß 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.

Endothelial maintenance in health and disease: Importance of sex differences.

The vascular endothelium has emerged as more than just an inert monolayer of cells lining the vascular bed. It represents the interface between the blood stream and vessel wall, and has a strategic role in regulating vascular homeostasis by the release of vasoactive substances. Endothelial dysfunction contributes to the development and progression of cardiovascular disease. Recognition of sex-specific factors implicated in endothelial cell biology is important for the identification of clinically relevant preventive and/or therapeutic strategies. This review aims to give an overview of the recent advances in understanding the importance of sex specific observations in endothelial maintenance, both in healthy and diseased conditions. The female endothelium is highlighted in the context of polycystic ovary syndrome and pre-eclampsia. Furthermore, sex differences are explored in chronic kidney disease, which is currently appreciated as one of public health priorities. Overall, this review endorses integration of sex analysis in experimental and patient-oriented research in the exciting field of vascular biology.