Karin Ruijtenbeek

Chronic Hypoxia Stimulates Periarterial Sympathetic Nerve Development in Chicken Embryo

BackgroundEpidemiological findings suggest an association between low-for-age birth weight and the risk to develop coronary heart diseases in adulthood. During pregnancy, an imbalance between fetal demands and supply may result in permanent alterations of neuroendocrine development in the fetus. We evaluated whether chronic prenatal hypoxia increases arterial sympathetic innervation. Methods and ResultsChicken embryos were maintained from 0.3 to 0.9 of the 21-day incubation period under normoxic (21% O2) or hypoxic conditions (15% O2). At 0.9 incubation, the degree of sympathetic innervation of the embryonic femoral artery was determined by biochemical, histological, and functional (in vitro contractile reactivity) techniques. Chronic hypoxia increased embryonic mortality (32% versus 13%), reduced body weight (21.9±0.4 versus 25.4±0.6 g), increased femoral artery norepinephrine (NE) content (78.4±9.4 versus 57.5±5.0 pg/mm vessel length), and increased the density of periarterial sympathetic nerve fibers (14.4±0.7 versus 12.5±0.6 counts/104 &mgr;m2). Arteries from hypoxic embryos were less sensitive to NE (pD2, 5.99±0.04 versus 6.21±0.10). In the presence of cocaine, however, differences in sensitivity were no longer present. In the embryonic heart, NE content (156.9±11.0 versus 108.1±14.7 pg/mg wet wt) was also increased after chronic hypoxia. ConclusionsIn the chicken embryo, chronic moderate hypoxia leads to sympathetic hyperinnervation of the arterial system. In humans, an analogous mechanism may increase the risk for cardiovascular disease in adult life.

Chronic Moderate Hypoxia and Protein Malnutrition Both Induce Growth Retardation, But Have Distinct Effects on Arterial Endothelium-Dependent Reactivity in the Chicken Embryo

Deviations in the rate of intrauterine growth may change organ system development, resulting in cardiovascular disease in adult life. Arterial endothelial dysfunction often plays an important role in these diseases. The effects of two interventions that reduce fetal growth, chronic hypoxia and protein malnutrition, on arterial endothelial function were investigated. Eggs of White Leghorn chickens were incubated either in room air or in 15% O2 from d 6 until d 19 of the 21-d incubation. Protein malnutrition was induced by removal of 10% of the total albumen content at d 0. In vitro reactivity of the femoral artery in response to vasodilators was measured at d 19. Both chronic hypoxia and protein malnutrition reduced embryonic body weight at d 19 by 14% without affecting relative brain weight. Chronic hypoxia or protein malnutrition did not change sensitivity to the exogenous nitric oxide donor, sodium nitroprusside (5.74 ± 0.15 versus 5.85 ± 0.23 and 6.05 ± 0.18 versus 6.01 ± 0.34, respectively). Whereas protein malnutrition did not modify arterial sensitivity to acetylcholine (7.00 ± 0.10 versus 7.12 ± 0.05), chronic hypoxia reduced sensitivity to this endothelium-dependent vasodilator (6.57 ± 0.07 versus 7.02 ± 0.06). In the presence of Nω-nitro-l-arginine methyl ester, this difference in sensitivity to acetylcholine was no longer apparent (6.31 ± 0.13 versus 6.27 ± 0.06), indicating that chronic exposure to hypoxia reduced sensitivity to acetylcholine by lowering nitric oxide release. In additional experiments, a decrease in basal nitric oxide release in arteries of 3- to 4-wk-old chickens that had been exposed to in ovo chronic hypoxia was observed (increase in K+ contraction: −0.16 ± 0.33 N/m versus 0.68 ± 020 N/m). Protein malnutrition and chronic hypoxia both induce disproportionate growth retardation, but only the latter impairs arterial endothelial function. Intrauterine exposure to chronic hypoxia induces changes in arterial endothelial properties that may play a role in the development of cardiovascular disease in adult life.

Foetale programmering: consequenties op volwassen leeftijd

SummaryEpidemiological studies have shown an association between non-infectious diseases of the adult and the quality of growth before and after birth. An inverse relation between low birth weight and systolic blood pressue in the adult was found and the risk for other types of cardiovascular diseases also seems to be increased following prenatal growth retardation. These studies have not yet been able to establish which factors are responsible for ‘fetal programming’. To elucidate the mechanisms, experimental animal models such as rats, guinea pigs, lambs, and chicken embryos are used in intervention studies. The possibility to induce intrauterine growth retardation in these animals by reducing the availability of nutients and oxygen, suggests the involvement of various stimuli in the process of fetal programming. Prenatal changes in the expression of growth factors, corticosteroid levels, glomeruli numbers, elasticity of the blood vessels and peri-arterial innervation, may, if permanently present, result in cardiovascular disease. Only when the mechanism behind fetal programming is understood, clinical treatment and preventive strategies can be determined.SamenvattingEpidemiologische onderzoeken tonen een verband aan tussen niet-infectieuze ziekten op volwassen leeftijd en de kwaliteit van de groei voor en na de geboorte. Bij volwassenen is een omgekeerde relatie tussen laag geboortegewicht en systolische bloeddruk gevonden, maar ook de kans op andere cardiovasculaire aandoeningen blijkt verhoogd te zijn na prenatale groeiretardatie. De vraag welke factor tijdens de zwangerschap verantwoordelijk is voor de ‘foetale programmering’, hebben de onderzoeken vooralsnog niet kunnen beantwoorden. Om het mechanisme op te helderen, wordt in interventieonderzoek gebruikgemaakt van diermodellen als ratten, cavias, lammeren en kippenembryos. Dat het mogelijk is om bij deze dieren intra-uteriene groeiretardatie te induceren door de beschikbaarheid van nutriënten en/of zuurstof te verlagen, suggereert dat verschillende factoren bij het proces van foetale programmering betrokken zijn. Prenataal ingezette veranderingen in de expressie van groeifactoren, corticosteroïdenconcentraties, aantallen glomeruli, elasticiteit van bloedvaten en arteriële bezenuwing zouden, indien permanent van aard, kunnen leiden tot cardiovasculaire aandoeningen. Slechts wanneer meer bekend is over het mechanisme van foetale programmering, kan in de kliniek een strategie voor behandeling en preventie worden ontwikkeld.

Direct Effects of Acute Hypoxia on the Reactivity of Peripheral Vessels of the Chick Embryo

Direct Effects of Acute Hypoxia on the Reactivity of Peripheral Vessels of the Chick Embryo