Mechanisms of endothelial dysfunction in resistance arteries from patients with end-stage renal disease.

Leanid Luksha,Peter Stenvinkel,Juan Jesús Carrero,Folke Hammarqvist,Karolina Kublickiene,Sandra T Davidge

doi:10.1371/journal.pone.0036056

Leanid Luksha, Peter Stenvinkel + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0036056

Copy DOI

Abstract

The study focuses on the mechanisms of endothelial dysfunction in the uremic milieu. Subcutaneous resistance arteries from 35 end-stage renal disease (ESRD) patients and 28 matched controls were studied ex-vivo. Basal and receptor-dependent effects of endothelium-derived factors, expression of endothelial NO synthase (eNOS), prerequisites for myoendothelial gap junctions (MEGJ), and associations between endothelium-dependent responses and plasma levels of endothelial dysfunction markers were assessed. The contribution of endothelium-derived hyperpolarizing factor (EDHF) to endothelium-dependent relaxation was impaired in uremic arteries after stimulation with bradykinin, but not acetylcholine, reflecting the agonist-specific differences. Diminished vasodilator influences of the endothelium on basal tone and enhanced plasma levels of asymmetrical dimethyl L-arginine (ADMA) suggest impairment in NO-mediated regulation of uremic arteries. eNOS expression and contribution of MEGJs to EDHF type responses were unaltered. Plasma levels of ADMA were negatively associated with endothelium-dependent responses in uremic arteries. Preserved responses of smooth muscle to pinacidil and NO-donor indicate alterations within the endothelium and tolerance of vasodilator mechanisms to the uremic retention products at the level of smooth muscle. We conclude that both EDHF and NO pathways that control resistance artery tone are impaired in the uremic milieu. For the first time, we validate the alterations in EDHF type responses linked to kinin receptors in ESRD patients. The association between plasma ADMA concentrations and endothelial function in uremic resistance vasculature may have diagnostic and future therapeutic implications.

Highlights

Adverse cardiovascular events are common complications of end-stage renal disease (ESRD) and these patients are more likely to die from cardiovascular disease (CVD) than from kidney failure [1]
Plasma levels of asymmetrical dimethyl L-arginine (ADMA), soluble vascular cell adhesion molecule-1, interleukin-6, pentraxin-3, high sensitivity C-reactive protein and lipoprotein(a) and triglycerides were elevated in ESRD
We show that reduced endothelium-derived hyperpolarizing factor (EDHF) type responses contribute markedly to endothelial dysfunction in ESRD

Summary

Introduction

Adverse cardiovascular events are common complications of end-stage renal disease (ESRD) and these patients are more likely to die from cardiovascular disease (CVD) than from kidney failure [1]. The underlying mechanisms that predispose ESRD patients to higher risk of CVD are incompletely understood, morphological and functional abnormalities of the endothelium may play an important role [2]. Endothelial dysfunction is considered an early marker of CVD [3], which facilitates the progress of atherosclerosis [4] and contributes to the development of hypertension through the enhancement of vascular resistance [5]. The contribution of NO to endothelium-dependent control of vascular tone is inversely associated with caliber of arteries. Another vasodilator, known as endothelium-derived hyperpolarizing factor (EDHF), seems to act as a predominant mediator of endothelium-dependent dilatation in resistance-size arteries. When deprivation of EDHF occurs, this may further aggravate endothelial dysfunction leading to enhanced blood pressure and impaired blood flow to target organs [13]

Methods

Results

Conclusion