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In preeclampsia, vasospasm, oxidative stress, endothelial dysfunction, and immune dysregulation are key mediators of maternal disease. A new time-of-disease treatment is needed with the potential to treat these areas of pathophysiology. A review of the literature has indicated that metabolites of the kynurenine pathway have the potential to; (i) induce vasorelaxation of resistance arteries and reduce blood pressure; (ii) exert antioxidant effects and reduce the effects of poly-ADP ribose polymerase activation (iii) prevent endothelial dysfunction and promote endothelial nitric oxide production; (iv) cause T cell differentiation into tolerogenic regulatory T cells and induce apoptosis of pro-inflammatory Th1 cells. This has led to the hypothesis that increasing Kynurenine pathway activity may offer a new treatment strategy for preeclampsia. • Vascular dysfunction, oxidative stress and immune dysregulation drive maternal preeclampsia. • Kynurenine causes vasorelaxation, counteracts oxidative stress and induces immunotolerance • We postulate increasing Kynurenine pathway activity may ameliorate drivers of maternal disease. • Extensive pre-clinical proof-of-principle and safety experiments will precede human treatment. [ABSTRACT FROM AUTHOR]

Objective. To determine if the phosphodiesterase type 5 inhibitor, sildenafil citrate improves endothelial-dependent relaxation of small arteries from women with preeclampsia. Methods. Myometrial and omental biopsies were taken from women participating in a randomized placebo-controlled trial using sildenafil citrate in women with preeclampsia. Vasoconstriction and endothelial-dependent relaxation of small arteries was measured utilizing wire myography. Results. Vasoconstriction and endothelial-dependent relaxation of myometrial and omental arteries were not altered in women taking sildenafil. Conclusion. Acute effects may have been lost as sildenafil administration occurred many hours prior to myography. Plasma sildenafil levels may have been lower than required for vascular response. [ABSTRACT FROM AUTHOR]

The ANP knockout mouse is reported to exhibit pregnancy-associated hypertension, proteinuria and impaired placental trophoblast invasion and spiral artery remodeling, key features of pre-eclampsia (PE). We hypothesized that these mice may provide a relevant model of human PE with associated fetal growth restriction (FGR). Here, we investigated pregnancies of ANP wild type (ANP(+/+)), heterozygous (ANP(+/-)) and knockout (ANP(-/-)) mice. Maternal blood pressure did not differ between genotypes (E12.5, E17.5), and fetal weight (E18.5) was unaffected. Placental weight was greater in ANP(-/-) versus ANP(+/+) mice. Therefore, in our hands, the ANP model does not express phenotypic features of PE with FGR. [ABSTRACT FROM AUTHOR]

Abstract: Control of vascular resistance and blood flow in the fetoplacental circulation is incompletely understood. Reactive oxygen species (ROS), physiological and pathophysiological regulators of vascular tone, are elevated in preeclampsia (PE), a disease of pregnancy characterized by increased fetoplacental vascular resistance. We tested the hypothesis that ROS modulate vascular reactivity in placental chorionic plate arteries. Wire myography was used to examine (1) the effects of acute exposure to ROS on arterial function in normal pregnancy and (2) the effects of maternal antioxidant supplementation on arterial reactivity in women at high risk for PE participating in the Vitamins in Pre-eclampsia (VIP) trial. ROS generated by xanthine plus xanthine oxidase enhanced basal tension, vasoconstriction in response to the thromboxane mimetic U46619, and relaxation in response to sodium nitroprusside. Hydrogen peroxide and peroxynitrite increased basal tone and relaxed preconstricted arteries (U44619), respectively. In women at risk for PE, chorionic plate artery constriction in response to U46619 was greater in the women receiving placebo compared to the women supplemented with the antioxidant vitamins C and E. ROS may regulate fetoplacental vascular resistance and blood flow in the short term, and chronic exposure to raised ROS could contribute to elevated fetoplacental vascular resistance in PE and fetal growth restriction (FGR). [Copyright &y& Elsevier]

Abstract: Objectives: In pre-eclampsia (PE), endothelium-dependent function of myometrial small arteries is markedly attenuated. The residual PE response is wholly NO mediated. We have previously demonstrated that PDE5 inhibition can improve endothelial function in myometrial small arteries from women with PE. We aimed to assess whether the effect of PDE5 inhibition in PE was myometrial artery specific. Study design: Small arteries were dissected from omental biopsies obtained at Caesarean section from normal pregnant women (NP, N = 20) and women with PE (N = 11). Chorionic plate small arteries were dissected from NP (N = 13) and PE (N = 11) placentae. Vasoconstriction (arginine vasopressin or thromboxane-mimetic U46619) and endothelial-dependent relaxation were assessed by wire and pressure myography. Constriction/relaxation curves were repeated post 1h incubation with PDE5 inhibitors UK-343664 or sildenafil citrate (0, 10 or 100nM). Results: Omental artery constriction was increased in PE. Omental vessel constriction was unaffected by PDE5 inhibition. Sildenafil citrate improved bradykinin-induced but not acetylcholine-induced relaxation of omental small arteries from NP women. PDE5 inhibition did not alter relaxation of omental arteries from women with PE. Placental small arteries were unaffected by PDE5 inhibition. Conclusion: Use of PDE5 inhibitors does not significantly alter endothelial-dependent relaxation in omental or placental small arteries from PE women. [Copyright &y& Elsevier]

Our aim was to compare placental chorionic plate small artery function in normal pregnancies and those complicated by preeclampsia and intrauterine growth restriction. In particular we wished to test the hypothesis that the constrictive potential of placental small arteries is modified in compromised pregnancy. Biopsies were obtained from term placentas from uncomplicated pregnancies and those affected by preeclampsia and intrauterine growth restriction. Small arteries from the chorionic plate were dissected free from surrounding tissue and studied using parallel wire myography. Placental small arteries developed maintained constrictions to arginine vasopressin and the thromboxane-mimetic U46619. Arterial maximal constriction was reduced in both preeclampsia and intrauterine growth restriction. This effect was agonist independent. In intrauterine growth restriction, placental small arteries showed decreased sensitivity to U46619 but not to arginine vasopressin. Human placental chorionic plate small artery vasoconstriction is significantly reduced in compromised pregnancy, a factor that may lead to altered blood flow within the fetoplacental circulation in these conditions. [ABSTRACT FROM AUTHOR]

Objective: In preeclampsia, endothelium-dependent function is markedly aberrant. Myometrial resistance arteries from women with preeclampsia show a minimal, wholly nitric oxide-mediated, bradykinin-induced relaxation. Our aim was to test that phosphodiesterase 5 (PDE5) inhibition could improve endothelium-dependent function in preeclampsia. Study design: Small arteries dissected from myometrial biopsies obtained at cesarean section from normal pregnant women (N = 22) or women with preeclampsia (N = 24) were mounted on wire or pressure myographs. Vessels were constricted (arginine vasopressin or U46619) and relaxed (bradykinin) before and after incubation with a PDE5 inhibitor, UK-343664. Results: Endothelium-dependent vasodilatation was decreased in vessels from women with preeclampsia. 100 nmol/L UK-343664 did not affect normal pregnant but significantly improved relaxation of the vessels from women with preeclampsia. Conclusion: A PDE5 inhibitor enhances endothelial function of myometrial vessels from women with preeclampsia, such that the behavior of these arteries approximates to those from normal women. These agents offer a potential therapeutic strategy for the management of preeclampsia. [ABSTRACT FROM AUTHOR]

Objectives: Preeclampsia (PE) is a multisystem disease unique to human pregnancy. Abnormal placentation results in placental hypoperfusion leading to the secretion of a factor(s) by the placenta. Our aim was to investigate whether neurokinin B (NKB) is the circulating factor associated with PE.Study Design: Vascular effects of NKB were assessed in blood vessels dissected from myometrial and omental biopsy specimens obtained at caesarean section from normal pregnant women (n = 26) or in mesenteric blood vessels obtained from nonpregnant female Wistar rats (n = 4).Results: Incubation with NKB did not alter endothelial-dependent relaxation of omental or myometrial arteries. NKB produced a dose-dependent relaxation in preconstricted omental arteries and veins. NKB did not affect vasoactive responsiveness of rat mesenteric arteries.Conclusion: We conclude from these observations that NKB is not the circulating factor associated with increased vascular resistance in PE. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Endothelial dysfunction is central to the pathogenesis of pre-eclampsia (PE). This study aimed to determine if maternal characteristics, such as age, parity, BMI, smoking status and obstetric history, which affect the risk of developing pre-eclampsia, influenced endothelial function in myometrial arteries taken during an uncomplicated pregnancy. Study design: As part of ongoing studies investigating endothelial function in normal and compromised pregnancies, myometrial vessels were isolated from biopsies taken at elective Caesarean section. A cohort of 119 women was identified and information regarding past pregnancy outcomes and medical history was obtained. Wire myography was used to compare endothelial-dependent relaxation in response to bradykinin between different patient groups. Results: Maternal age, parity and a history of miscarriage did not affect endothelial-dependent relaxation of myometrial small arteries. Attenuated endothelial-dependent relaxation was seen in vessels taken from women with elevated BMI and enhanced relaxation was seen in women who had smoked during pregnancy. Vessels isolated from women with a history of past pregnancy complications did not show any significant difference in endothelial-dependant relaxation compared to women with uncomplicated histories. Conclusion: Maternal factors may influence endothelial function in the absence of pregnancy complications. Endothelial-dependent relaxation of myometrial arteries, isolated from multiparous women with an uncomplicated index pregnancy, is comparable between women with and without a history of pregnancy complications. [Copyright &y& Elsevier]