We investigated an effect of uraemia on structural and functional features of human resistance vasculature. Arteries (? 200 ?m) isolated from subcutaneous fat biopsies obtained from 35 ESRD (end-stage renal disease) patients starting peritoneal dialysis and 30 matched controls were studied using isolated small artery bioassays. Flow-mediated dilatation was attenuated in ESRD patients compared with controls. NO (nitric oxide) contribution to flow was lacking in ESRD patients, but present in the controls. ADMA (asymmetrical dimethyl L-arginine) levels were higher in the ESRD group compared with the control group. Dilatation in response to acetylcholine was reduced in ESRD patients compared with controls, but response to NO donor was similar. Expression of nitrotyrosine and heat shock proteins 70 and 27, but not 90, was increased in arteries from ESRD patients compared with controls. Arterial remodelling was absent in ESRD patients. There was no difference between the groups in myogenic tone, vascular reactivity or sensitivity to several vasoconstrictors. Arterial distensibility, reflecting passive properties of the vascular wall, was reduced in ESRD patients compared with controls. Exclusion of ESRD patients with diabetes and/or cardiovascular disease from analyses had no influence on the main findings. Thus we propose that uraemia has a strong impact on endothelial function and passive properties of the arterial wall of human peripheral resistance vasculature. The reduced contribution of NO to flow stimulus via enhanced nitrosative stress and higher plasma concentrations of ADMA may suggest potential mechanisms behind endothelial dysfunction in the resistance peripheral circulation in ESRD.
This ex vivo study focuses on the mechanisms of endothelium-dependent dilatation in the uterine circulation of normal pregnancy (n = 12) and in women with preeclampsia (n = 12). Arteries (internal diameter, ?250 ?m) isolated by myometrial biopsy from women undergoing planned cesarean delivery or delivery as a result of the deterioration of preeclampsia were studied using a wire myograph. Bradykinin-induced dilatation was assessed in the presence and/or absence of pharmacological inhibitors to determine the contribution of nitric oxide and endothelium-derived hyperpolarizing factor (EDHF), as well as that of EDHF-mediated pathways such as myoendothelial gap junctions (MEGJs) and products of arachidonic acid, H(2)O(2) and cytochrome P450 2C9 (CYP2C9). Transmission electron microscopy was used to visualize morphological prerequisites for MEGJs. In normal pregnancy, EDHF through MEGJs appeared to be a predominant mediator conferring endothelium-dependent relaxation in small myometrial arteries. In preeclampsia, bradykinin-induced relaxation was reduced via compromised EDHF-type responses, in which the contribution of MEGJs became negligible. The attenuated role of MEGJs to endothelium-dependent relaxation was partly compensated through the contribution of H(2)O(2) or other endothelium-derived relaxing factors. CYP2C9 products of arachidonic acid had no effect on EDHF-type relaxation in arteries of women with normal pregnancy or with preeclampsia. We suggest that EDHF-type responses via MEGJs are primarily targeted in small myometrial arteries in women with preeclampsia. This could significantly contribute to the impaired uteroplacental blood flow in this disorder.
The endothelium maintains vascular homeostasis through the release of active vasodilators. Although nitric oxide (NO) is recognized as the primary factor at level of conduit arteries, increased evidence for the role of another endothelium-derived vasodilator known as endothelium-derived hyperpolarizing factor (EDHF) has accumulated in the last years. Despite the ongoing debate of its intriguingly variable nature and mechanisms of action, the contribution of EDHF to the endothelium-dependent relaxation is currently appreciated as an important feature of "healthy" endothelium. Since EDHFs contribution is greatest at level of small arteries, the changes in the EDHF action are of critical importance for the regulation of organ blood flow, peripheral vascular resistance and blood pressure, and particularly when production of NO is compromised. Moreover, depending on the type of cardiovascular disorders altered EDHF responses may contribute to, or compensate for endothelial abnormalities associated with pathogenesis of certain disease. Consequently, an identification of vessel-specific nature of EDHF, its modulation of biological activity by selective activators or inhibitors might have a significant impact to our understanding of vascular maintenance in health and disease, and provide basis for novel therapeutic strategies. In this review, the contemporary knowledge about mechanism, function and dysfunction of EDHF-typed responses is systemized. The relevance of this part of endothelium-dependent relaxation for main cardiovascular complications is under discussion. Several issues, like gender differences and role of estrogen for EDHF contribution are summarized for the first time. Authors based on their own experience and data of literature propose several guidelines for future research in the field of EDHF.
Protective role of estrogens (E2) against cardiovascular disease has been appreciated for many years until the equivocal results of cardiovascular outcomes in clinical trials on hormone replacement therapy were reported. Although new ongoing trials aim to resolve these discrepancies, it is obvious that cardiovascular effects of E(2) are complex and diverse. To understand further the cardiovascular effects of E(2), the detailed knowledge on the specific role of both classical estrogen receptor (ER) subtypes and G protein-coupled receptor-30 in the vasculature are of importance. In this article, we review the current knowledge about the pattern of ERalpha and ERbeta expression in human vasculature, the genomic and non-genomic cardiovascular effects of E(2)versus subtype selective ERalpha and ERbeta stimulation on isolated arteries and in different knockout animal models. The results indicate that although ERalpha and ERbeta are expressed in the endothelium and media of human arteries, there is no definite evidence for predominant expression of one over another, the pattern depends on vascular bed, sex and diseased condition. Data from the experiments on isolated arteries and in ER knockout animal models may indicate that activation of specific ER subtypes could provide additional cardiovascular protective effects. However, a clear role for each ERs have to be finalised with focus on mechanisms and by exploring the potential of ERs-selective agonists for clinical utility.
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.
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