Recent data suggest that the decrease in EDH may be the result of disturbances in MEGJs [78, 79]. Alterations in endothelium-dependent relaxation have also been investigated in the rat RUPP model of preeclampsia. Deficits in endothelium-dependent relaxation have been noted in uterine [5, 114] and mesenteric arteries; reports range from a significant reduction in relaxation [110, 113] to no change relative to normal-pregnant animals [6]. In the aorta, a substantial decrease in relaxation has been noted in some studies [110], while others report a more subtle change [31, 91]. Interestingly, Morton and colleagues recently found that impaired relaxation in aortas from RUPP dams was accompanied

by increased levels of LOX-1 and eNOS [91]. Ex vivo experiments NU7441 using vessels and/or plasma from preeclamptic pregnancies have also provided insight into the mechanisms of vascular dysfunction. Incubation of resistance vessels from normal-pregnant women with plasma from women with preeclampsia causes a decrease in endothelium-dependent relaxation in response to bradykinin [56]. Microparticles isolated from plasma of women with preeclampsia, rather than the plasma itself, have been identified BAY 57-1293 molecular weight as the instigator of dysfunction [142]. A recent study found that plasma-mediated dysfunction is augmented in isolated arteries by

exposure to oxLDL [42]. Furthermore, inhibition of LOX-1 can prevent this deficit, protecting endothelial function [42]. Interestingly, plasma collected from pregnant women who would later develop preeclampsia has the capacity to reduce endothelium-dependent

relaxation in vessels from women with uncomplicated pregnancies, highlighting the importance of Low-density-lipoprotein receptor kinase circulating factors well before clinical manifestation and diagnosis [95]. Consistent with human studies, in the rat RUPP model, vessels from normal-pregnant animals show impaired endothelium-dependent vasodilatation following incubation with RUPP plasma [148]. Experiments in both humans and rats have found that plasma-mediated endothelial dysfunction is prevented by incubating vessels in the presence of a PARP inhibitor, suggesting a role for vascular dysfunction mediated by oxidative stress-stimulated PARP activation [32, 147]. Preeclampsia is a complex, multifactorial disorder and while its etiology remains elusive, the maternal syndrome, characterized by widespread vascular dysfunction, stems from circulating factors released as a consequence of placental ischemia/hypoxia. Disparity in the production of pro- and antiangiogenic factors, excessive inflammation, and the induction of oxidative stress within the endothelium are major contributors to endothelial dysfunction. Interestingly, research shows that women that have had preeclampsia continue to show signs of endothelial dysfunction postpartum, leaving them at increased risk for CVD later in life ([2, 20], reviewed in [47]).