Maternal n-3 PUFA deficiency alters uterine artery remodeling and placental epigenome in the mice.

The maternal n-3 polyunsaturated fatty acid (PUFA) deficiency on decidual vascular structure and angiogenesis in mice placenta was investigated. Namely, we studied uterine artery remodeling, fatty acid metabolism, and placental epigenetic methylation in this animal model. Weanling female Swiss albino mice were fed either alpha-linolenic acid (18:3 n-3, ALA) deficient diets (0.13% energy from ALA) or a sufficient diet (2.26% energy from ALA) throughout the study. The dietary n-3 PUFA deficiency altered uteroplacental morphology and vasculature by reversing luminal to vessel area and increased luminal wall thickness at 8.5-12.5gD. Further, placentas (F0 and F1) showed a significant decrease in the expression of VCAM1, HLAG proteins and an increase in MMP9, KDR expression. The conversion of ALA to long-chain (LC) n-3 PUFAs was significantly decreased in plasma and placenta during the n-3 deficiency state. Reduced n-3 LCPUFAs increased the placental expression of intracellular proteins FABP3, FABP4, and ADRP to compensate decreased availability of these fatty acids in the n-3 deficient mice. The N-3 PUFA deficiency significantly increased the 5-methylcytosine levels in the placenta but not in the liver. The alteration in DNA methylation continued to the next generation in the placental epigenome with augmented expression of DNMT3A and DNMT3B. Our study showed that maternal n-3 PUFA deficiency alters placental vascular architecture and induces epigenetic changes suggesting the importance of n-3 PUFA intake during the development of the fetus. Moreover, the study shows that the placenta is the susceptible target for epigenetic alteration in maternal deficiency n-3 fatty acids.

Postpartum Persistence of Maternal Uterine Vascular Gestational Adaptation in Rodents.

Although pregnancy has long-lasting consequences for maternal vascular health, little is known about vascular changes postpartum (PP). Focusing on the uterine circulation, which undergoes unique structural and functional adaptation during gestation, we hypothesized that most pregnancy-induced changes would return to baseline PP, with minimal hysteresis. Large (main; MUA) and small (segmental; SUA) uterine arteries from adult Sprague Dawley rats (n = 42) were evaluated 1 and 4 weeks PP (1PP, 4PP) and compared with those of late-pregnant (LP, day 21) and age-matched non-pregnant (NP) animals. Some comparisons were extended to mesenteric arteries to evaluate differences between reproductive and systemic vessels. Pregnancy-induced axial elongation regressed > 80% 1PP in MUAs and SUAs, although some minimal hysteresis remained 4PP. Circumferential growth was slower to regress, with no reductions in lumen diameter or media thickness 1PP; values returned to (MUA) or approached (SUA) NP values by 4PP. Changes in vascular smooth muscle cell cross-sectional area-a measure of hypertrophy-paralleled those in lumen diameter. Mesenteric and uterine artery compliance diverged during gestation, and continued to do so PP. Decreased MUA compliance 4PP was supported by an increased collagen:elastin ratio. Adrenergic sensitivity increased in uterine, and decreased in mesenteric arteries during pregnancy, and returned to NP values 4PP in both types of vessels. MUA α-1 adrenoceptor expression tracked along with sensitivity. Thus, postpartum adaptation varies by both parameter and vessel type. While many parameters regressed postpartum, alterations in compliance did not, suggesting that matrix changes may have long-term consequences for maternal vascular function and health.

Effect of the Hemoxygenase-Carbon Monoxide (HO-CO) System on the Reactivity of Uterine Artery Branches in Rats.

First to fourth-order branches of the uterine artery in sexually mature female Wistar rats were studied by biomicroscopy. After administration of a CO donor hemin (60 mM), the diameters of large uterine branches with a well-developed muscle layer markedly increased, while the increase in diameter of small vessels with one often interrupted layer of smooth muscle cells increased insignificantly. Zinc protoporphyrin IX (30 mM) in all cases blocked this effect. However, zinc protoporphyrin IX does not affect NO-mediated reaction of the branches of the uterine artery caused by administration of L-arginine (60 mM), and L-NAME did not significantly affect reactivity of uterine artery branches associated with the hemoxygenase-CO system. In contrast to NO, CO produced less potent and rapid, but more sustained effect. The target for the hemoxygenase-CO system is mainly arteries with developed muscular layer, while the target for the NO synthase-NO is small vessels where endothelium plays a Rdecisive role in the regulation of vasomotor reactions.

Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes.

The term placental bed was coined to describe the maternal-fetal interface (ie, the area in which the placenta attaches itself to the uterus). Appropriate vascularization of this area is of vital importance for the development of the fetus; this is why systematic investigations of this area have now been carried out. Initially, the challenge was the identification and classification of the various successive branching of uterine arteries in this area. These vessels have a unique importance because failure of their physiological transformation is considered to be the anatomical basis for reduced perfusion to the intervillous space in women with preeclampsia, fetal growth restriction, preterm labor, preterm premature rupture of membranes, abruptio placentae, and fetal death. To investigate in depth the pathophysiology of the placental bed, some 60 years ago, a large number of placental bed biopsies, as well as of cesarean hysterectomy specimens with placenta in situ, from both early and late normotensive and hypertensive pregnancies, were carefully dissected and analyzed. Thanks to the presence of a series of specific physiological changes, characterized by the invasion and substitution of the arterial intima by trophoblast, this material allowed the identification in the placental bed of normal pregnancies of the main vessels, the uteroplacental arteries. It was then discovered that preeclampsia is associated with defective or absent transformation of the myometrial segment of the uteroplacental arteries. In addition, in severe hypertensive disease, atherosclerotic lesions were also found in the defective myometrial segment. Finally, in the basal decidua, a unique vascular lesion, coined acute atherosis, was also identified This disorder of deep placentation, coined defective deep placentation, has been associated with the great obstetrical syndromes, grouping together preeclampsia, intrauterine growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and abruptio placentae. More recently, simplified techniques of tissue sampling have been also introduced: decidual suction allows to obtain a large number of decidual arteries, although their origin in the placental bed cannot be determined. Biopsies parallel to the surface of the basal plate have been more interesting, making possible to identify the vessels' region (central, paracentral, or peripheral) of origin in the placental bed and providing decidual material for immunohistochemical studies. Finally, histochemical and electron microscopy investigations have now clarified the pathology and pathogenetic mechanisms underlying the impairment of the physiological vascular changes.

[Prognostic value of uteroplacental circulation impairment in 1st trimester of pregnancy in patients with complicated obstetric history].

UNLABELLED: One of the urgent problems of modern obstetrics is the early detection of irregularities in the development of the uteroplacental vessels system in patients with severe disorders in the history. AIM: To evaluate the predictive value of re-development of obstetric pathology on the basis of the uterine artery Doppler on 11-14 weeks of pregnancy. PATIENTS AND METHODS: 410 patients in I trimester of pregnancy were examined with fetal growth restriction, preeclampsia and/or fetal death and/or a history of preterm delivery were. The influence of physical factors and obstetric history on the state of uterine blood flow in the I trimester of pregnancy was studied. RESULTS: The optimal Doppler indexes was calculated; a high predictive ability of the pulsation index in the uterine arteries with respect to pregnancy complications with early clinical manifestation, severe preeclampsia and combined obstetric complications was detected. CONCLUSIONS: Our data support the possibility of preclinical diagnosis of obstetrical complications in patients with complicated obstetric history.

Pregnancy-induced remodelling and enhanced endothelium-derived hyperpolarization-type vasodilator activity in rat uterine radial artery: transient receptor potential vanilloid type 4 channels, caveolae and myoendothelial gap junctions.

In pregnancy, the vasculature of the uterus undergoes rapid remodelling to increase blood flow and maintain perfusion to the fetus. The present study determines the distribution and density of caveolae, transient receptor potential vanilloid type 4 channels (TRPV4) and myoendothelial gap junctions, and the relative contribution of related endothelium-dependent vasodilator components in uterine radial arteries of control virgin non-pregnant and 20-day late-pregnant rats. The hypothesis examined is that specific components of endothelium-dependent vasodilator mechanisms are altered in pregnancy-related uterine radial artery remodelling. Conventional and serial section electron microscopy were used to determine the morphological characteristics of uterine radial arteries from control and pregnant rats. TRPV4 distribution and expression was examined using conventional confocal immunohistochemistry, and the contribution of endothelial TRPV4, nitric oxide (NO) and endothelium-derived hyperpolarization (EDH)-type activity determined using pressure myography with pharmacological intervention. Data show outward hypertrophic remodelling occurs in uterine radial arteries in pregnancy. Further, caveolae density in radial artery endothelium and smooth muscle from pregnant rats was significantly increased by ~94% and ~31%, respectively, compared with control, whereas caveolae density did not differ in endothelium compared with smooth muscle from control. Caveolae density was significantly higher by ~59% on the abluminal compared with the luminal surface of the endothelium in uterine radial artery of pregnant rats but did not differ at those surfaces in control. TRPV4 was present in endothelium and smooth muscle, but not associated with internal elastic lamina hole sites in radial arteries. TRPV4 fluorescence intensity was significantly increased in the endothelium and smooth muscle of radial artery of pregnant compared with control rats by ~2.6- and 5.5-fold, respectively. The TRPV4 signal was significantly higher in the endothelium compared with the smooth muscle in radial artery of both control and pregnant rats, by ~5.7- and 2.7-fold, respectively. Myoendothelial gap junction density was significantly decreased by ~37% in radial artery from pregnant compared with control rats. Pressure myography with pharmacological intervention showed that NO contributes ~80% and ~30%, and the EDH-type component ~20% and ~70% of the total endothelium-dependent vasodilator response in radial arteries of control and pregnant rats, respectively. TRPV4 plays a functional role in radial arteries, with a greater contribution in those from pregnant rats. The correlative association of increased TRPV4 and caveolae density and role of EDH-type activity in uterine radial artery of pregnant rats is suggestive of their causal relationship. The decreased myoendothelial gap junction density and lack of TRPV4 density at such sites is consistent with their having an integral, albeit complex, interactive role in uterine vascular signalling and remodelling in pregnancy.

Strenuous exercise during pregnancy: is there a limit?

OBJECTIVE: The purpose of this study was to evaluate fetal responses to strenuous exercise in physically active and inactive women. STUDY DESIGN: Forty-five healthy women (15 who were nonexercisers, 15 who were regularly active, 15 who were highly active) underwent a peak treadmill test at 28 weeks' gestation to 32 weeks 6 days' gestation. Fetal well-being (umbilical artery Doppler indices, fetal heart tracing/rate, biophysical profile [BPP]) was evaluated before and after exercise. Uterine artery Doppler scans were also obtained. RESULTS: Umbilical and uterine artery Doppler indices were similar among activity groups and did not change with exercise (P > .05). BPP and fetal heart tracings were reassuring in all groups. However, subgroup analyses showed transient fetal heart rate decelerations after exercise and elevated umbilical and uterine artery Doppler indices in 5 highly active women. After this, BPP and fetal heart tracings were reassuring. CONCLUSION: Overall fetal well-being is reassuring after short-duration, strenuous exercise in both active and inactive pregnant women. A subset of highly active women experienced transient fetal heart rate decelerations and Doppler changes immediately after exercise. Athletes may push beyond a threshold intensity at which fetal well-being may be compromised. However, potential impact on neonatal outcomes is unknown.

Endothelial nitric oxide synthase deficiency reduces uterine blood flow, spiral artery elongation, and placental oxygenation in pregnant mice.

Preeclampsia is associated with impaired uteroplacental adaptations during pregnancy and abnormalities in the endothelial NO synthase (eNOS)-NO pathway, but whether eNOS deficiency plays a causal role is unknown. Thus, the objective of the current study was to determine the role of eNOS in the mother and/or conceptus in uteroplacental changes during pregnancy using eNOS knockout mice. We quantified uterine artery blood flow using microultrasound, visualized the uteroplacental vasculature using vascular corrosion casts, and used pimonidazole and hypoxia-inducible factor 1α immunohistochemistry as markers of hypoxia in the placentas of eNOS knockout mice versus the background strain, C57Bl/6J (wild type). We found that increases in uteroplacental blood flow, uterine artery diameter, and spiral artery length were reduced, and markers of placental hypoxia in the junctional zone were elevated in late gestation in eNOS knockout mice. Both maternal and conceptus genotypes contributed to changes in uterine artery diameter and flow. Despite placental hypoxia, placental soluble fms-like tyrosine kinase 1 and tumor necrosis factor-α mRNA, and in maternal plasma, soluble fms-like tyrosine kinase 1 were not elevated in eNOS knockout mice. Thus, our results show that both eNOS in the mother and the conceptus contribute to uteroplacental vascular changes and increased uterine arterial blood flow in normal pregnancy.