Differential mechanisms of endothelium-dependent vasodilator responses in human myometrial small arteries in normal pregnancy and pre-eclampsia

Abstract

Pre-eclampsia is a pregnancy-specific disorder associated with hypertension and proteinuria, characterized by alterations in endothelial cell function. In the present study we have compared responses to the endothelium-dependent vasodilator, bradykinin, in small myometrial arteries from normal pregnant and non-pregnant women and women with pre-eclampsia, in order to assess the relative contributions of nitric oxide, endothelium-derived hyperpolarizing factor (EDHF) and prostanoids in mediating endothelium-dependent vasodilatation. Bradykinin-induced concentration-dependent relaxation in arteries isolated from the three subject groups did not differ with regard to sensitivity or maximum response. Responses to bradykinin in all three groups were unaffected by cyclo-oxygenase inhibition alone, and were similarly unaffected by partial depolarization. The nitric oxide synthase (NOS) inhibitor, N-nitro-l-arginine methyl ester, significantly attenuated the responses to bradykinin in arteries from non-pregnant women and almost abolished responses in arteries from women with pre-eclampsia. However, in arteries from normal pregnant women, bradykinin-induced responses were maintained in the presence of NOS inhibition. Inhibition of NOS combined with partial depolarization abolished responses to bradykinin in these vessels. These results support the suggestion that, in the absence of NO, an EDHF can mediate vasodilator responses to bradykinin during normal pregnancy, an effect not apparent in arteries from non-pregnant women or women with pre-eclampsia. The up-regulation of EDHF-type function may represent a vascular adaptation to normal pregnancy that is absent in pre-eclampsia, and this might contribute to the clinical features of the disease.

Excessive stimulation of poly(ADP‐ribosyl)ation contributes to endothelial dysfunction in pre‐eclampsia

“…In previous studies, we have demonstrated an attenuation in the endothelium-dependent relaxation of subcutaneous and myometrial vessels isolated from women with preeclampsia (Ashworth et al, 1997;Kenny et al, 2002). We have also shown that we can mimic this response through incubation of normal vessels with low levels of plasma from pre-eclamptic donors (Ashworth et al, 1998;Hayman et al, 2000).…”

“…In this study, we have confirmed this finding, but unlike previous investigations, we have also defined a mechanism to explain these plasma-induced anomalies. Previous investigations have demonstrated attenuated endothelium-dependent relaxation in subcutaneous and myometrial vessels isolated from women with pre-eclampsia (McCarthy et al, 1993;Knock & Poston, 1996;Ashworth et al, 1997;Vedernikov et al, 2001;Kenny et al, 2002). This attenuation has been mimicked in normal vessels by incubation with low levels of plasma from pre-eclamptic subjects (Ashworth et al, 1998;Hayman et al, 2000).…”

“…There is overwhelming evidence linking pre-eclampsia with the development of endothelial dysfunction (Roberts et al, 1989;McCarthy et al, 1993;Roberts & Redman, 1993;Friedman et al, 1995;Ashworth et al, 1997;Kenny et al, 2002). However, the cellular mechanisms involved have yet to be established.…”

Pre-eclampsia is associated with sleep-disordered breathing and endothelial dysfunction

“…The disease is characterised by generalised vasoconstriction, an increase in peripheral resistance, platelet activation, reduced plasma volume and organ hypoperfusion [25,26]. The aetiology is still unclear, although recent evidence suggests that increments in blood pressure may reflect ED, the inability of the blood vessel endothelial cells to release relaxing factors that cause vasodilatation [27,28].…”

Detection and Identification of Novel Metabolomic Biomarkers in Preeclampsia

“…The clinical syndrome of preeclampsia results from widespread changes in endothelial cell function in both small and large vessels. [5][6][7] There is currently no accurate way of predicting preeclampsia, and consequently, clinicians are unable to offer either targeted surveillance or potential preventative therapies to those at greatest risk. Widespread plasma alterations precede the clinical onset of preeclampsia and, therefore, there is intense interest in the identification of predictive biomarkers.…”