Vascular tone regulation in renal interlobar arteries of male rats is dysfunctional after intrauterine growth restriction

Intrauterine growth restriction (IUGR) due to an adverse intrauterine environment predisposes to arterial hypertension and loss of kidney function. Here we investigated whether vascular dysregulation in renal interlobar arteries (RIA) may contribute to hypertensive glomerular damage after IUGR. In rats, IUGR was induced by bilateral uterine vessel ligation. Offspring of non-operated rats served as controls (C). From postnatal day (PND) 49, blood pressure was telemetrically recorded. On PND 70, we evaluated contractile function in RIA and mesenteric arteries (MA). Additionally, blood, urine and glomerular parameters and renal collagen deposition were analyzed. IUGR-RIA not only showed loss of stretch activation in 9/11 arteries and reduced stretch-induced myogenic tone, but also a shift of the concentration-response relation of acetylcholine-induced relaxation towards lower concentrations. However, IUGR-RIA also exhibited augmented contractions through phenylephrine (PE). Systemic mean arterial pressure [mean differences 4.8 (daytime) and 5.7 mmHg (night)], mean glomerular area (IUGR, 9754 ± 338; C, 8395 ± 227 µm2) and urinary protein/creatinine ratio (IUGR, 1.67 ± 0.13; C, 1.26 ± 0.10 g/g) were elevated after IUGR. We conclude that male IUGR rat offspring may have increased vulnerability towards hypertensive glomerular damage due to loss of myogenic tone and augmented endothelium-dependent relaxation in RIA.

The Effect of Hesperidin on BDNF/TrkB Signaling Pathway and Oxidative Stress Parameters in the Cerebral Cortex of the Utero-placental Insufficiency Fetal Rat Model

Introduction: Uteroplacental insufficiency (UPI) produces critical neurodevelopmental problems affecting the intrauterine growth restricted (IUGR) in offspring. In this study, it was aimed to investigate the possible neuroprotective roles of hesperidin (Hes) on the fetal cerebral cortex of the UPI rat model. Methods: In this experimental study, 40 pregnant Wistar rats (age:~40-day old, weight: 180±10g) were randomly divided into 5 groups (n=8), includeing control (normal saline, orally), UPI+NS (uterine vessel ligation+normal saline, orally), UPI+HES25, UPI+HES50 and UPI+HES100 (uterine vessel ligation+25, 50 and 100 mg/kg hesperidin, orally). After being anesthetized by ketamine and xylazine, UPI was induced by permanent bilateral closure of the uterine vessels on gestation day (GD) 18. From GD15, the Hes/NS- treated groups received Hesperidin/normal saline until GD21. On GD21, uterus, placenta and fetus were dissected out and weighed. The oxidative stress parameters, including catalase (CAT) activity, malondialdehyde (MDA), and total antioxidant capacity (TAC) in the fetal cerebral cortex were measured. The expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) was assessed by RT qPCR methods. Data were analyzed by ANOVA and Tukey’s post hoc test. Results: Findings showed a significant difference in the uterine and fetus weight in Hes-treated mothers (p< 0.05). In fetus, Hes reduced MDA, and increased CAT activity and TAC (p ˂ 0.001 in the UPI+Hes100 group compared to the UPI+NS group). UPI reduced BDNF and TrkB mRNA expression compared to the control group (p< 0.05). Also, Significant increases in BDNF and TrkB mRNA expression were observed after administration of Hes in the fetal cerebral cortex of the UPI rat model, in a dose dependent manner (p< 0.05). Conclusion: Hesperidin; as a neuroprotective and antioxidant agent; accelerates BDNF-TrkB signaling pathway and suppresses oxidative stress parameters in the cerebral cortex of the UPI rat model.

Autophagy in the uterine vessel microenvironment: Balancing vasoactive factors

Autophagy, which has the literal meaning of self-eating, is a cellular catabolic process executed by arrays of conserved proteins in eukaryotes. Autophagy is dynamically ongoing at a basal level, presumably in all cells, and often carries out distinct functions depending on the cell type. Therefore, although a set of common genes and proteins is involved in this process, the outcome of autophagic activation or deficit requires scrutiny regarding how it affects cells in a specific pathophysiological context. The uterus is a complex organ that carries out multiple tasks under the influence of cyclic changes of ovarian steroid hormones. Several major populations of cells are present in the uterus, and the interactions among them drive complex physiological tasks. Mouse models with autophagic deficits in the uterus are very limited, but provide an initial glimpse at how autophagy plays a distinct role in different uterine tissues. Herein, we review recent research findings on the role of autophagy in the uterine mesenchyme in mouse models.

Treadmill Exercise before and during Pregnancy Improves Bone Deficits in Pregnant Growth Restricted Rats without the Exacerbated Effects of High Fat Diet

Growth restriction programs adult bone deficits and increases the risk of obesity, which may be exacerbated during pregnancy. We aimed to determine if high-fat feeding could exacerbate the bone deficits in pregnant growth restricted dams, and whether treadmill exercise would attenuate these deficits. Uteroplacental insufficiency was induced on embryonic day 18 (E18) in Wistar Kyoto (WKY) rats using bilateral uterine vessel ligation (restricted) or sham (control) surgery. The F1 females consumed a standard or high-fat (HFD) diet from 5 weeks, commenced treadmill exercise at 16 weeks, and they were mated at 20 weeks. Femora and plasma from the pregnant dams were collected at post-mortem (E20) for peripheral quantitative computed tomography (pQCT), mechanical testing, histomorphometry, and plasma analysis. Sedentary restricted females had bone deficits compared to the controls, irrespective of diet, where such deficits were prevented with exercise. Osteocalcin increased in the sedentary restricted females compared to the control females. In the sedentary HFD females, osteocalcin was reduced and CTX-1 was increased, with increased peak force and bending stress compared to the chow females. Exercise that was initiated before and continued during pregnancy prevented bone deficits in the dams born growth restricted, whereas a HFD consumption had minimal bone effects. These findings further highlight the beneficial effects of exercise for individuals at risk of bone deficits.

Spontaneous uterine vessel perforation in late pregnancy following in vitro fertilisation: a rare cause of near miss maternal morbidity and fetal death

Spontaneous perforation of uterine vessels causing hemoperitoneum in pregnancy is rare and is associated with high perinatal and maternal mortality and morbidity. However, for the clinician identification of aetiology with ongoing resuscitation is important in order to affect the proper treatment. Case report: We report a case of spontaneous hemoperitoneum in pregnancy following IVF conception due to ruptured uterine vein successfully managed with emergency laparotomy and repair of the uterine vessel. Conclusion: Clinicians should be aware of such rare and potentially fatal complications after IVF, because early diagnosis and management in these cases can yield a favourable maternal and perinatal outcome.

Puberty onset is delayed following uteroplacental insufficiency and occurs earlier with improved lactation and growth for pups born small

Being born small programs adult diseases later in life, with the early postnatal growth rate in growth-restricted offspring playing a role in the reduction of the risk of disease in adulthood. In addition, early postnatal growth is critical for puberty onset (PO). Using cross-fostering, we determined the effects of growth restriction and prenatal and postnatal environments on PO and sex steroids. Bilateral uterine vessel ligation (Restricted) or sham surgery (Control), performed on Gestational Day 18 in Wistar-Kyoto rats induced fetal growth restriction. Control, Reduced (Control litter size reduced to five pups) and Restricted pups were cross-fostered onto different Control (normal lactation) or Restricted (impaired lactation) mothers on Day 1. The day of vaginal opening (females) and balanopreputial separation (males) characterised PO. Blood was sampled for sex steroid and leptin analysis. Restricted pups were born lighter than Controls (P < 0.05). PO was delayed by 3.4–4 days in Restricted-on-Restricted males and females (P < 0.05). Plasma leptin concentrations at PO were lower in both sexes in all groups compared with Restricted-on-Control and Control-on-Control (P < 0.05). PO occurred earlier in Restricted-on-Control (~2 days) with normal leptin concentrations and accelerated growth compared with Restricted-on-Restricted (P < 0.05). Testosterone concentrations were lower in male Restricted-on-Restricted than Control-on-Control at 6 months (P < 0.05). Restricted-on-Restricted females had lower progesterone at PO compared with Control-on-Control (P < 0.05). Female Restricted-on-Restricted had lower oestradiol, with Restricted-on-Control having higher testosterone concentrations at 6 months than Control-on-Control (P < 0.05). Growth restriction reduced postnatal growth and leptin concentrations, delaying PO in both sexes and programming altered sex steroids. This highlights the importance of the interaction between prenatal and postnatal growth in the programming of adult reproductive status.

Reduced Perinatal Leptin Availability May Contribute to Adverse Metabolic Programming in a Rat Model of Uteroplacental Insufficiency

Leptin availability in perinatal life critically affects metabolic programming. We tested the hypothesis that uteroplacental insufficiency and intrauterine stress affect perinatal leptin availability in rat offspring. Pregnant rats underwent bilateral uterine vessel ligation (LIG; n = 14), sham operation (SOP; n = 12), or no operation (controls, n = 14). Fetal livers (n = 180), placentas (n = 180), and maternal blood were obtained 4 hours (gestational day [E] 19), 24 hours (E20), and 72 hours (E22) after surgery. In the offspring, we took blood samples on E22 (n = 44), postnatal day (P) 1 (n = 29), P2 (n = 16), P7 (n = 30), and P12 (n = 30). Circulating leptin (ELISA) was significantly reduced in LIG (E22, P1, P2) and SOP offspring (E22). Postnatal leptin surge was delayed in LIG but was accelerated in SOP offspring. Placental leptin gene expression (quantitative RT-PCR) was reduced in LIG (E19, E20, E22) and SOP (E20, E22). Hepatic leptin receptor (Lepr-a, mediating leptin degradation) gene expression was increased in LIG fetuses (E20, E22) only. Surprisingly, hypoxia-inducible factors (Hif; Western blot) were unaltered in placentas and were reduced in the livers of LIG (Hif1a, E20; Hif2a, E19, E22) and SOP (Hif2a, E19) fetuses. Gene expression of prolyl hydroxylase 3, a factor expressed under hypoxic conditions contributing to Hif degradation, was increased in livers of LIG (E19, E20, E22) and SOP (E19) fetuses and in placentas of LIG and SOP (E19). In summary, reduced placental leptin production, increased fetal leptin degradation, and persistent perinatal hypoleptinemia are present in intrauterine growth restriction offspring, especially after uteroplacental insufficiency, and may contribute to perinatal programming of leptin resistance and adiposity in later life.