The intra-hepatic umbilical-Porto-systemic venous shunt and fetal growth.

OBJECTIVE: The fetal liver circulation has an important role in fetal growth. The intra-hepatic Umbilical-Porto-Systemic Venous Shunt (IHUPSVS) causes a reduction of the umbilical blood flow to the liver and has been reported to have a restrictive effect on fetal growth. The aim of this study was to evaluate the effect of IHUPSVS on fetal growth. METHODS: We conducted a retrospective cohort study of IHUPSVS diagnosed between 2001 and 2019. IHUPSVS was defined as any abnormal communication between any branch of the portal vein and hepatic vein. Pre- and postnatal characteristics were collected from medical files and compared between cases with fetal growth restriction (FGR) and those appropriate for gestational age (AGA). RESULTS: Twenty-five fetuses were included in the study. Eighteen (72%) had last estimated fetal weight and birth weight below the 10th centile, four (16%) of them between the third and fifth centile, and 11 (44%) below the third centile. Median gestational age at delivery was lower for FGR than AGA fetuses (37 vs. 38 weeks, p = 0.034) and rate of preterm delivery was higher (38.9 vs. 14.3, P = 0.24). Four cases had associated structural anomalies (2 in each group), and two had minor genetic aberrations (1 in each group). CONCLUSIONS: Growth restriction is prevalent in fetuses with IHUPSVS, suggesting that fetal growth should be monitored. In equal measure, in cases with growth restriction, especially without other apparent cause, an intrahepatic shunt should be looked for.

A Protocol for a Novel Human Ex Vivo Model of Aneurysm.

Aortic aneurysm rupture is a significant cause of premature mortality worldwide. Although animal models exist, some frequently experience aortic rupture and sudden death. An alternative approach is therefore required that would use human material to aid translation. Accordingly, we present an optimized and validated protocol to isolate human umbilical cord arteries and their subsequent deployment within a bioreactor. Consequently, this reproducible ex vivo human model of aneurysm can be used for pathogenesis studies and accompanying assessment of potential novel therapeutics.

Umbilical artery histomorphometry: a link between the intrauterine environment and kidney development.

Prematurity is a risk factor for hypertension, vascular stiffness, nephron deficit and adult onset cardiorenal disease. The vascular tree and kidneys share morphogenic drivers that promote maturation in utero before 36 weeks of gestation. Vascular elastin accrual terminates after birth leaving collagen to promote vascular stiffness. Our objective was to determine if the histomorphometry of the umbilical artery, an extension of the aorta, parallels nephron mass across gestational age groups. From a cohort of 54 newborns, 32 umbilical cord specimens were adequate for evaluation. The umbilical cord was sectioned, stained with trichrome, and digitalized. Muscular and collagenous areas of the umbilical artery were measured in pixels using the Image J 1.48q software. Total kidney volume was measured by ultrasound and factored by body surface area (TKV/BSA). The umbilical artery total area was significantly greater in term v. preterm infants (9.3±1.3 v. 7.0±2.0 mm2; P<0.05) and increased with gestational age; while the percent muscular and collagen areas were independent of gestational age (R 2=0.04; P=ns). Percent muscular area correlated positively with TKV/BSA (r=0.53; P=0.002); while an increase in collagen correlated inversely with kidney mass (r=-0.53; P=0.002). In conclusion, an enhanced % muscular area and presumed vascular elasticity was associated with increased renal mass in all infants. Umbilical artery histomorphometry provides a link between the intrauterine environment, vascular and kidney development.

Sympathetic Innervation Promotes Arterial Fate by Enhancing Endothelial ERK Activity.

RATIONALE: Arterial endothelial cells are morphologically, functionally, and molecularly distinct from those found in veins and lymphatic vessels. How arterial fate is acquired during development and maintained in adult vessels is incompletely understood. OBJECTIVE: We set out to identify factors that promote arterial endothelial cell fate in vivo. METHODS AND RESULTS: We developed a functional assay, allowing us to monitor and manipulate arterial fate in vivo, using arteries isolated from quails that are grafted into the coelom of chick embryos. Endothelial cells migrate out from the grafted artery, and their colonization of host arteries and veins is quantified. Here we show that sympathetic innervation promotes arterial endothelial cell fate in vivo. Removal of sympathetic nerves decreases arterial fate and leads to colonization of veins, whereas exposure to sympathetic nerves or norepinephrine imposes arterial fate. Mechanistically, sympathetic nerves increase endothelial ERK (extracellular signal-regulated kinase) activity via adrenergic α1 and α2 receptors. CONCLUSIONS: These findings show that sympathetic innervation promotes arterial endothelial fate and may lead to novel approaches to improve arterialization in human disease.

Repercusión en los resultados neonatales del intervalo de tiempo de nacimiento entre gemelos / Effect of twin-to-twin delivery time interval on neonatal outcome

Objetivo. Evaluar los factores que pueden influir sobre el intervalo de tiempo de nacimiento entre gemelos y sobre el resultado neonatal a corto plazo del segundo gemelo. Material y métodos. Se realizó un estudio descriptivo retrospectivo a través de la base de datos informatizada y la revisión de las historias clínicas de las pacientes atendidas en el Hospital Universitario Miguel Servet desde enero de 2005 hasta diciembre de 2007. Se ha realizado un análisis estadístico para determinar los factores que potencialmente pueden afectar el intervalo de tiempo de nacimiento entre gemelos incluyendo: características maternas, edad gestacional, tipo de parto, discordancia de pesos fetales, pH de arteria umbilical y puntuaciones en el test de Apgar. Resultados. De los 13.340 partos registrados durante el periodo de estudio, 206 gestaciones gemelares se ajustaron a los criterios de inclusión. La mayoría de los segundos gemelos (79,6%) nacieron en los 5 min siguientes al parto del primer gemelo. Las características maternas como la edad, la paridad, la obesidad y el tabaquismo no se relacionaron con el incremento del intervalo al nacimiento. Un mayor intervalo se asoció a un aumento de riesgo de puntuaciones bajas en el test de Apgar y a un descenso de los valores de pH de arteria umbilical. El parto instrumental se asoció a un incremento del intervalo de tiempo. Conclusión. Basándonos en nuestros datos y los reflejados por estudios previos podemos decir que el intervalo de tiempo al nacimiento entre gemelos parece ser un factor de riesgo independiente para un resultado neonatal adverso (AU)

Objective. To evaluate the factors influencing twin-to-twin delivery time interval and the short-term outcome of the second twin. Material and methods. We performed a retrospective, descriptive study by reviewing a computerized database and the medical records of pregnant women attending the Miguel Servet University Hospital from January 2005 to December 2007. A statistical analysis was performed to determine the factors potentially affecting twin-to-twin delivery time interval, including maternal characteristics, gestational age, mode of delivery, fetal weight discordance, umbilical artery pH and Apgar score. Results. Of the 13,430 deliveries registered during the study period, 206 twin pregnancies met the inclusion criteria. Most (79.6%) of the second twins were born within 5min of delivery of the first twin. Maternal characteristics such as age, parity, obesity and smoking were not related to twin-to-twin delivery time interval. A longer time interval was associated with an increased risk of low Apgar scores and a decline in umbilical artery pH in the second twin. Vaginal operative delivery was associated with an increased time interval. Conclusion. Based on our data and the results of previous studies, twin-to-twin delivery time interval seems to be an independent risk factor for adverse neonatal outcome (AU)

The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions.

Lenalidomide (Revlimid) is approved for the treatment of transfusion-dependent patients with anemia due to low- or intermediate-1-risk Myelodysplastic Syndromes (MDS) associated with a del 5q cytogenetic abnormality with or without additional cytogenetic abnormalities, and in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy. Previous reports suggest that lenalidomide is anti-angiogenic and this property appears to be related to efficacy in patients with MDS. We have investigated the effect of lenalidomide on the formation of microvessels in a novel in vitro angiogenesis assay utilizing human umbilical arterial rings and in a capillary-like cord formation assay using cultured primary endothelial cells. We found that lenalidomide consistently inhibits both sprout formation by arterial rings and cord formation by endothelial cells in a dose-dependent manner. We also found an inhibitory effect of lenalidomide on the associations between cadherin 5, beta-catenin and CD31, adherens junction proteins whose interaction is critical for endothelial cell cord formation. Furthermore, lenalidomide inhibited VEGF-induced PI3K-Akt pathway signaling, which is known to regulate adherens junction formation. We also found a strong inhibitory effect of lenalidomide on hypoxia-induced endothelial cell formation of cords and HIF-1 alpha expression, the main mediator of hypoxia-mediated effects and a key driver of angiogenesis and metastasis. Anti-metastatic activity of lenalidomide in vivo was confirmed in the B16-F10 mouse melanoma model by a >40% reduction in melanoma lung colony counts versus untreated mice. Our results suggest that inhibitory effects on microvessel formation, in particular adherens junction formation and inhibition of hypoxia-induced processes support a potential anti-angiogenic and anti-metastatic mechanism for this clinically active drug.

[Vascular smooth muscle cells from human umbilical artery undergo osteoblast differentiation and calcification in vitro].

To research if the vascular smooth muscle cells (VSMCs) from human umbilical artery undergo osteoblast differentiation spontaneously in vitro. The growth curve of vascular smooth muscle cells from human umbilical artery was obtained by MTT method. The course of multicell nodule formation spontaneously by VSMCs was observed morphologically. The apoptosis of VSMCs in the nodules was detected by Hoechst 33258 and TUNEL methods respectively. The expression of alkaline phosphotase in the nodules was detected by immunohistochemical method. And the calcification was studied with transmission electron microscope and by alizarin red S respectively. We found that the umbilical artery smooth muscle cells confluenced after 7 days of passage and exhibited typical "hill and valley" pattern under light microscope. The cells grew into aggregation and formed nodules at the "hill" region with culture-time prolongation. After 4-5 weeks culture, these nodules built up and calcified spontaneously. We also found alkaline phosphotase expression and apoptosis of VSMCs in these nodules at the same time. We conclude that the vascular smooth muscle cells from human umbilical artery just like from aortic artery can undergo osteoblast differentiation spontaneously in vitro, and apoptosis participate this procedure probably.

Intermediate filament proteins in developing human arteries.

The distribution of intermediate filament proteins in adult human blood vessels and in human fetal elastic arteries is relatively well-known. However, the distribution of these proteins in the course from neonate to adult has not been established. In this investigation, human postnatal arteries were studied with immunohistochemistry, using antibodies targeted on the intermediate filament proteins desmin, vimentin and cytokeratins 8, 18 and 19. Vimentin was present in most smooth muscle cells in all vessels and at all ages. The proportions of desmin-expressing cells increased in the elastic arteries during the first year of life and was higher in the pulmonary trunk than in the aorta. In the muscular arteries, the proportion of desmin-labelled cells increased in the coronary and the deep femoral arteries, but remained constant in the renal and the cerebral arteries. Cytokeratins were detected in the pulmonary trunk earlier than in the aorta. Cytokeratins were present throughout the wall of the ductus arteriosus, but desmin was present only in some cells. Thus, there are postnatal changes in the distribution of intermediate filament proteins in the elastic arteries and in some muscular arteries, whereas the intermediate filament pattern remains unchanged in other muscular arteries.

A study of the ultrastructure of developing human umbilical vessels.

Electron microscopic techniques were used to examine the ultrastructure of developing human umbilical arteries and vein (8-12, 13-17 and 37-40 wk gestational age). These showed that with increasing age there is (1) an increase in the size of the lumen and the thickness of the media; (2) an increase in the ratio of contractile smooth muscle phenotypic cells; (3) an increase in the myofilament content of the smooth muscle cells and the number of Weibel-Palade bodies; (4) a decrease in the glycogen content; (5) an appearance of microvilli on the luminal surface of the endothelium. Lipid vesicles, nerves and vasa vasorum were not observed in any region of the umbilical vein or arteries.