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Cardiovascular physiology during fetal development and implications for tissue engineering.

Shear stress in fluid dynamics has a well-known impact on vascular cell morphology, proliferation, orientation, and the organization and composition of extracellular matrix. There is an increasing interest in the field of tissue engineering to use defined shear stress in bioreactors for tissue conditioning and guided tissue formation. Especially for cardiovascular structures like heart valves or blood vessels, the type and appropriate amount of shear stress needed to improve tissue formation remains speculative. The authors believe that fetal-like conditions may be more optimal for new tissue formation in a bioreactor. The purpose of this review is to delineate parameters of cardiovascular physiology during embryonic and fetal development that may have a potential impact on the design and setting of bioreactors for cardiovascular tissue engineering.

Biomedical Engineering↗

Expression of the mouse Delta1 gene during organogenesis and fetal development.

Cell-to-cell communication mediated by the evolutionary conserved Notch signalling pathway regulates cell fate decisions and patterning in various tissues in diverse organisms (Artavanis-Tsakonas et al., 1995, Science 268, 225-232). Signalling between neighboring cells is transduced by binding of DSL and Notch proteins which interact as ligand (DSL) and receptor (Notch). Mouse Delta1 (delta-like 1; Dll1) encodes one of the four known mammalian DSL proteins and is essential for normal somitogenesis and neuronal differentiation. Here, we describe Delta1 expression during organogenesis and fetal development using the highly sensitive histochemical detection of the lacZ gene product expressed from a targeted Delta1:lacZ knock-in allele (Dll1(lacZ)). We find that Delta1 is expressed in epithelial ducts of several organs, skeletal and smooth muscles, the central nervous system, as well as some sensory epithelia.

Animals↗

Alpha(1H) mRNA in single skeletal muscle fibres accounts for T-type calcium current transient expression during fetal development in mice.

Calcium channels are essential for excitation-contraction coupling and muscle development. At the end of fetal life, two types of Ca(2+) currents can be recorded in muscle cells. Whereas L-type Ca(2+) channels have been extensively studied, T-type channels have been poorly characterized in skeletal muscle. We describe here the functional and molecular properties of T-type calcium channels in developing mouse skeletal muscle. The T-type current density increased transiently during prenatal myogenesis with a maximum at embryonic day E16 followed by a drastic decrease until birth. This current showed similar electrophysiological and pharmacological properties at all examined stages. It displayed a wide window current centred at about -35 and -55 mV in 10 and 2 mM external Ca(2+), respectively. Activation and inactivation kinetics were fast (3 and 16 ms, respectively). The current was inhibited by nickel and amiloride with an IC(50) of 5.4 and 156 microM, respectively, values similar to those described for cloned T-type alpha(1H) channels. Whole muscle tissue RT-PCR analysis revealed mRNAs corresponding to alpha(1H) and alpha(1G) subunits in the fetus but not in the adult. However, single-fibre RT-PCR demonstrated that only alpha(1H) mRNA was present in prenatal fibres, suggesting that the alpha(1G) transcript present in muscle tissue must be expressed by non-skeletal muscle cells. Altogether, these results demonstrate that the alpha(1H) subunit generates functional T-type calcium channels in developing skeletal muscle fibres and suggest that these channels are involved in the early stages of muscle differentiation.

Animals↗

The effect of adult hemoglobin on red blood cell nitric oxide levels during fetal development.

OBJECTIVE: To compare the levels of S-nitrosohemoglobin (HbSNO) at different gestational ages in newborn infants and correlate the levels of HbSNO with HbA and HbF. METHOD: Cord blood samples of 22 newborn infants of different gestational ages (25-41 weeks) were analyzed. The levels of HbF and HbA were determined by HPLC and of HbSNO by chemiluminescence. RESULTS: The level of HbSNO varied from 28.1 to 145.3 nM. There was a significant correlation with gestational age (r(2) = 0.5469, p < 0.0001) and with the relative amount of HbA (r(2) = 0.8144, p < 0.0001). CONCLUSION: The increases in HbSNO in fetal red cells is directly related to the relative amount of HbA.

Chromatography, High Pressure Liquid↗

[Fetal development].

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Embryonic and Fetal Development↗

Synthesis and stability of retinal photoreceptor mRNAs are coordinately regulated during bovine fetal development.

Steady state photoreceptor specific mRNA levels in bovine retina were studied during fetal maturation for five gene transcripts, including rhodopsin, arrestin (S-antigen), rod alpha-subunit of transducin, interphotoreceptor retinoid-binding protein (IRBP) and rod alpha-subunit of cGMP phosphodiesterase in order to understand mechanisms of gene regulation during photoreceptor development. A 10-15-fold increase in each transcript level begins between 5.5 and 6 months of gestation for each gene, suggesting a single coordinate induction event at this time. Quantitative analysis of transcriptional rates for each gene by nuclear run-on also reveals a coordinate increase at approximately the same time, demonstrating that induction is achieved by transcriptional activation. Interestingly, however, gene specific transcription rates in the pre-induction retina do not appear to parallel mRNA steady state levels. During fetal development neither the transcript level of each gene relative to the others nor relative mRNA turnover rates change substantially after the induction event at 5.5-6.0 months. However, at earlier times all genes exhibit higher mRNA turnover, implying that differential mRNA stability may also play an important role in determining steady-state levels.

3',5'-Cyclic-GMP Phosphodiesterases↗

Effects of CKD-602, a new camptothecin anticancer agent, on pregnant does and embryo-fetal development in rabbits.

CKD-602 is a newly developed camptothecin anticancer agent. Preclinical studies suggest that it may have greater antitumor activity and lower toxicity than other camptothecin anticancer agents. The potential of CKD-602 to induce developmental toxicity was investigated in the New Zealand White rabbit. Seventy-two artificially inseminated females (artificial insemination=day 0) were distributed among three treatment groups and a control group. CKD-602 was at dose levels of 0, 0.024, 0.048, or 0.096 mg x kg(-1) x day(-1) administered intravenously to pregnant does from days 6 to 18 of gestation. All does were subjected to caesarean section on day 28 of gestation. At 0.096 mg x kg(-1) x day(-1), 2 cases of abortion and 3 cases of death in pregnant rabbits were found in late gestation. In addition, an increase in the embryonic resorptions and a decrease in the litter size were found. At 0.048 mg x kg(-1) x day(-1), a single doe aborted on gestational day 26. An increase in the embryonic resorptions and fetal morphological alterations and a decrease in the litter size were also found. There were no signs of maternal toxicity or developmental toxicity at 0.024 mg x kg(-1) x day(-1). The results show that 13-day repeated intravenous dose of CKD-602 during the major organogenetic period in rabbits produces increased incidence of abortion and death, increased number of embryonic resorptions and fetal morphological alterations, and decreased litter size at dose levels of above 0.048 mg x kg(-1) x day(-1). In the current experimental conditions, the no-observed-adverse-effect levels (NOAELs) of CKD-602 are considered to be 0.048 mg x kg(-1) x day(-1) for does and 0.024 mg x kg(-1) x day(-1) for embryo-fetal development.

Abnormalities, Drug-Induced↗

N-acetyl-beta-glucosaminidase of lymphocytes in the premature infant with special reference to the fetal development of the lysosomas apparatus.

N-acetyl-beta-glucosaminidase activity was determined in peripheral blood lymphocytes by means of Hayashi's cytochemical method in 50 premature infants born between the 21st and 37th weeks of gestation. The lymphocytes exhibited three types of enzymatic cytochemical reaction, i.e. granular, diffuse and mixed (both granular and diffuse). The total count of enzyme-positive lymphocytes was significantly lower in the group of premature infants born between the 21st and 28th weeks of gestation as compared with those born later. This difference was due to the smaller numbers of enzyme-positive lymphocytes with granular reaction type in the group of more immature infants. The formation of enzyme-positive lysosomal granules within the lymphocyte cytoplasm during the last months of fetal development has been suggested and the relationship between the enzymatic equipment of lymphocyte lysosomes and immune response discussed.

Acetylglucosaminidase↗

Feedback control of glucocorticoid production is established during fetal development.

BACKGROUND: Glucocorticoids are involved in the regulation of metabolic, immunological, and developmental processes. Their synthesis is tightly controlled by feedback regulation through the hypothalamus-pituitary-adrenal (HPA) axis, allowing the organism to respond to stress in an adequate manner and to adapt to new situations. Disturbance of these regulatory mechanisms leads to major human diseases. By generating mice with a targeted mutation in the glucocorticoid receptor (GR) locus, it was possible to analyze the mechanism by which glucocorticoids control the HPA axis, under conditions where at least part of the feedback control was absent early in development. MATERIALS AND METHODS: RNase-protection and in situ hybridization assays were used to compare messenger RNA (mRNA) levels of genes involved in the control of the HPA axis in both GR-mutant and wild-type animals. RESULTS: Negative feedback regulation of the HPA axis by glucocorticoids, which is established around Day E16.5 of embryonic development in wild-type mice, does not occur in GR-mutants, resulting in an increased expression of proopiomelanocortin mRNA in the anterior lobe of the pituitary and of corticotropin-releasing hormone mRNA in the paraventricular nucleus of the hypothalamus. However, the expression of both arginine vasopressin and mineralocorticoid receptor in the brain is not affected. In the neurointermediate lobe of the pituitary, expression of the proopiomelanocortin gene was inversely regulated, compared with its expression in the anterior lobe. CONCLUSIONS: GR-dependent regulation of the HPA axis is established during fetal development, suggesting that maternal factors have an important role in influencing the HPA axis of the adult offspring.

Animals↗

trans Fatty acids: infant and fetal development.

This review evaluates scientific data associated with the possibility that trans fatty acids compromise fetal and infant early development. Concerns have been triggered by research that has heightened our awareness of the importance of n-3 and n-6 fatty acids; shown that trans fatty acids inhibit delta6 desaturation of linoleic acid; identified trans fatty acid isomers in fetal, infant, and maternal tissues; and reported an inverse association between the trans fatty acid content of tissue lipids and measures of growth and development. Animal studies provide little evidence that trans fatty acids influence growth, reproduction, or gross aspects of fetal development. However, these models may not have been appropriate for addressing all the subtle effects that influence development of human infant retinal, neural, or brain function. Human studies are hampered by the complexity of the interrelations among nutritional, genetic, and environmental factors and by ethical considerations that constrain the research design. Existing data have not established a causal relation between trans fatty acid intake and early development. Conclusions cannot be drawn from the possible association found between trans fatty acid exposure and lower n-3 and n-6 long-chain polyunsaturated fatty acids and growth because of confounding factors. Few studies addressed the question of whether trans fatty acids adversely affect human fetal growth. One study reported a correlation between the trans fatty acid content of plasma and birth weight of preterm infants and one study reported a relation between preterm births and the trans fatty acid content of maternal plasma. Limited associative data have addressed whether trans fatty acids adversely affect fetal and infant neurodevelopment and growth. The interpretation of existing research and development of recommendations should be done cautiously. Suggestions for research to clarify these issues are made.

Child↗

Effects of psychologic stress on fetal development and pregnancy outcome.

Data from animal studies show that maternal stress is associated with disturbances in pregnancy outcomes and offspring development and behavior, possibly as a result of permanent structural and functional changes termed "early-life programming." There is growing interest in whether similar relationships are present in humans. Here we review recent significant findings from the literature on the impact of prenatal psychologic stressors on pregnancy outcome and offspring development, with a particular focus on the developing brain. Relevant papers were searched using PubMed, and reference lists from obtained articles were checked. In humans, prenatal stress is associated with pregnancy complications, developmental, cognitive, and behavioral disorders, and possible onset of psychopathology in later life. In contrast to the available research done in animals, virtually nothing is known about the effects of prenatal stress on morphologic fetal brain development, and the mechanisms underlying subsequent associated behavioral changes.

Animals↗