STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): An international consortium of randomised placebo-controlled trials

Background: Severe, early-onset fetal growth restriction due to placental insufficiency is associated with a high risk of perinatal mortality and morbidity with long-lasting sequelae. Placental insufficiency is the result of abnormal formation and function of the placenta with inadequate remodelling of the maternal spiral arteries. There is currently no effective therapy available. Some evidence suggests sildenafil citrate may improve uteroplacental blood flow, fetal growth, and meaningful infant outcomes. The objective of the Sildenafil TheRapy In Dismal prognosis Early onset fetal growth Restriction (STRIDER) collaboration is to evaluate the effectiveness of sildenafil versus placebo in achieving healthy perinatal survival through the conduct of randomised clinical trials and systematic review including individual patient data meta-analysis.  Methods: Five national/bi-national multicentre randomised placebo-controlled trials have been launched. Women with a singleton pregnancy between 18 and 30 weeks with severe fetal growth restriction of likely placental origin, and where the likelihood of perinatal death/severe morbidity is estimated to be significant are included. Participants will receive either sildenafil 25 mg or matching placebo tablets orally three times daily from recruitment to 32 weeks gestation.  Discussion: The STRIDER trials were conceived and designed through international collaboration. Although the individual trials have different primary outcomes for reasons of sample size and feasibility, all trials will collect a standard set of outcomes including survival without severe neonatal morbidity at time of hospital discharge. This is a summary of all the STRIDER trial protocols and provides an example of a prospectively planned international clinical research collaboration. All five individual trials will contribute to a pre-planned systematic review of the topic including individual patient data meta-analysis

Salt, aldosterone, and the renin-angiotensin system in pregnancy

This chapter reviews physiological changes in volume and osmolality in normal pregnancy, as well as alterations in volume associated with preeclampsia. There is a marked stimulation of the renin–angiotensin–aldosterone (RAA) system and a rise in the plasma concentration during normal pregnancy. In contrast, plasma volume and components of the RAA system decreased preeclampsia. Importantly, activating autoantibodies to the angiotensin II type I receptor (AT1-AA) are present in preeclampsia. There is an evolving literature on the role of inflammatory cells and cytokines in contributing to preeclampsia by leading to production of the AT1-AA, which is discussed in this chapter

Mechanisms of uterine artery dysfunction in pregnancy complications

Pregnancy is a unique condition, and the vascular processes that are required for this undertaking are both complex and extensive. In this review, we discuss the vascular adaptations which occur in the maternal uterine arterial bed to maintain blood supply to the fetal-placental unit. In complicated pregnancies, inadequate remodeling of the uterine arteries, hormonal imbalances, and pre-existing conditions such as obesity, hypertension, diabetes etc. may lead to maladaptations of the uterine vasculature that includes increased vasoconstriction and endothelial dysfunction. Ultimately, uterine artery dysfunction results in increased vascular resistance impeding blood flow to the fetal-placental unit and limiting fetal growth and development. A strong association exists between poor fetal development in utero and later life health issues, which can include obesity, poor neurological development, and enhanced susceptibility to cardiovascular disease. Therefore, the detrimental outcomes of a complicated pregnancy are far-reaching and significantly impact the health of the population as a whole. Many treatment options to improve maternal uterine artery function and ameliorate the impact on the fetus are being considered. A particular difficulty in treating complicated pregnancies is the presence of not 1 but (at least) 2 patients. Novel approaches are required to successfully improve pregnancy outcomes and minimize the impact on later life health.Jude S. Morton, Alison S. Care, and Sandra T. Davidg

Supplementary Material for: Estradiol Modulates Tumor Necrosis Factor-Induced Endothelial Inflammation: Role of Tumor Necrosis Factor Receptor 2

The sex hormone estradiol (E₂) appears to mediate both anti-atherogenic and pro-inflammatory effects in premenopausal women, suggesting a complex immunomodulatory role. Tumor necrosis factor (TNF) is a key pro-inflammatory cytokine involved in the pathogenesis of atherosclerosis and other inflammatory diseases. Alterations at the TNF receptors (TNFRs) and their downstream signaling/transcriptional pathways can affect inflammatory responses. Given this background, we hypothesized that chronic E₂ exposure would alter endothelial inflammatory response involving modulation at the levels of TNFRs and signaling pathways. HUVECs were used as the model system. Pre-treatment with E₂ did not significantly alter TNF-induced upregulation of pro-inflammatory molecules ICAM-1 (3–6 times) and VCAM-1 (5–7 times). However, pharmacological inhibition of transcriptional pathways suggested a partial shift from NF-ĸB (from 97 to 64%) towards the JNK/AP-1 pathway in ICAM-1 upregulation on E₂ treatment. In contrast, VCAM-1 expression remained NF-ĸB dependent in both control (∼96%) and E₂ treated (∼85%) cells. The pro-inflammatory TNF effects were mediated by TNFR1. Interestingly, E₂ pre-treatment increased TNFR2 levels in these cells. Concomitant TNFR2 activation (but not TNFR1 activation alone) led to the shift towards JNK/AP-1-mediated ICAM-1 upregulation in E₂-treated cells, suggesting the effects of chronic E₂ to be dependent on TNFR2 signaling

Increased susceptibility to cardiovascular disease in offspring born from dams of advanced maternal age

Poster - T-177Christy-Lynn M Cooke, Alison S Care, Jude S Morton, Amin Shah, Laura M Reyes, Sandra T Davidg

Reduction in regulatory T cells in early pregnancy causes uterine artery dysfunction in mice

Preeclampsia, fetal growth restriction, and miscarriage remain important causes of maternal and perinatal morbidity and mortality. These complications are associated with reduced numbers of a specialized T lymphocyte subset called regulatory T cells (Treg cells) in the maternal circulation, decidua, and placenta. Treg cells suppress inflammation and prevent maternal immunity toward the fetus, which expresses foreign paternal alloantigens. Treg cells are demonstrated to contribute to vascular homeostasis, but whether Treg cells influence the vascular adaptations essential for a healthy pregnancy is unknown. Thus, using a mouse model of Treg-cell depletion, we investigated the hypothesis that depletion of Treg cells would cause increased inflammation and aberrant uterine artery function. Here, we show that Treg-cell depletion resulted in increased embryo resorption and increased production of proinflammatory cytokines. Mean arterial pressure exhibited greater modulation by NO in Treg cell-deficient mice because the L-NG-nitroarginine methyl ester-induced increase in mean arterial pressure was 46% greater compared with Treg cell-replete mice. Uterine artery function, which is essential for the supply of nutrients to the placenta and fetus, demonstrated dysregulated hemodynamics after Treg-cell depletion. This was evidenced by increased uterine artery resistance and pulsatility indices and enhanced conversion of bET-1 (big endothelin-1) to the active and potent vasoconstrictor, ET-1 (endothelin-1). These data demonstrate an essential role for Treg cells in modulating uterine artery function during pregnancy and implicate Treg-cell control of maternal vascular function as a key mechanism underlying normal fetal and placental development.Alison S. Care, Stephane L. Bourque, Jude S. Morton, Emma P. Hjartarson, Sarah A. Robertson and Sandra T. Davidg

Sex-specific effects of advanced maternal age on cardiovascular function in aged adult rat offspring

Pregnancy at an advanced maternal age has an increased risk of complications for both the mothers and their offspring. We have previously shown that advanced maternal age in a rat model leads to poor fetal outcomes, maternal vascular dysfunction and hypertension, concordant with findings in humans. Moreover, offspring from aged dams had sex-specific cardiovascular dysfunction in young adulthood. Yet, the detrimental impact of aging on the cardiovascular system of the offspring in this model is unknown. We hypothesized that offspring born to aged dams (9.5-10 months old) would have impaired cardiovascular function at 12 months of age. Echocardiographic data revealed signs of mild left ventricular (LV) diastolic dysfunction in only male offspring from aged dams (Isovolumetric relaxation time (IVRT); young 34.27±2.04 vs. aged dam 27.61±0.99 msec; P<0.01 and E'/A'; young 1.08±0.04 vs. aged dam 0.96±0.02; P<0.05). In young adulthood (4 months of age), we previously showed that male, but not female, offspring born from aged dams had impaired recovery from ischemia/reperfusion (I/R) injury. Aging did not alter the susceptibility of female offspring to I/R injury. Interestingly, wire myography data revealed that male offspring from aged dams had enhanced vascular sensitivity to methacholine (MCh pEC50: young 7.4±0.08 vs. aged dam 7.9±0.11; P=0.007) due, in part, to increased prostaglandin-mediated vasodilation. Despite intact endothelium-dependent relaxation, female offspring from aged dams had elevated systolic blood pressure (young 125.3±4.2 mmHg vs. aged dam 144.0±6.9 mmHg, P=0.03). These data highlight sex-specific mechanisms underlying cardiovascular programming in offspring born to dams of advanced age. KEYWORDS: advanced maternal age; cardiovascular dysfunction; developmental programming; offspring agingAmin Shah, Christy-Lynn M. Cooke, Raven D. Kirschenman, Anita L. Quon, Jude S. Morton, X Alison S. Care and Sandra T. Davidg

Perinatal resveratrol supplementation to spontaneously hypertensive rat dams mitigates the development of hypertension in adult offspring

This study was undertaken to determine whether perinatal maternal resveratrol (Resv)--a phytoalexin known to confer cardiovascular protection--could prevent the development of hypertension and improve vascular function in adult spontaneously hypertensive rat offspring. Dams were fed either a control or Resv-supplemented diet (4 g/kg diet) from gestational day 0.5 until postnatal day 21. Indwelling catheters were used to assess blood pressure and vascular function in vivo; wire myography was used to assess vascular reactivity ex vivo. Perinatal Resv supplementation in dams had no effect on fetal body weights, albeit continued maternal treatment postnatally resulted in growth restriction in offspring by postnatal day 21; growth restriction was no longer evident after 5 weeks of age. Maternal perinatal Resv supplementation prevented the onset of hypertension in adult offspring (-18 mm Hg; P=0.007), and nitric oxide synthase inhibition (with L-NG-nitroarginine methyl ester) normalized these blood pressure differences, suggesting improved nitric oxide bioavailability underlies the hemodynamic alterations in the Resv-treated offspring. In vivo and ex vivo, vascular responses to methylcholine were not different between treatment groups, but prior treatment with L-NG-nitroarginine methyl ester attenuated the vasodilation in untreated, but not Resv-treated adult offspring, suggesting a shift toward nitric oxide-independent vascular control mechanisms in the treated group. Finally, bioconversion of the inactive precursor big endothelin-1 to active endothelin-1 in isolated mesenteric arteries was reduced in Resv-treated offspring (-28%; P<0.05), and this difference could be normalized by L-NG-nitroarginine methyl ester treatment. In conclusion, perinatal maternal Resv supplementation mitigated the development of hypertension and causes persistent alterations in vascular responsiveness in spontaneously hypertensive rats.Alison S. Care, Miranda M. Sung, Sareh Panahi, Ferrante S. Gragasin, Jason R.B. Dyck, Sandra T. Davidge and Stephane L. Bourqu