Fetal hypoxia is a common complication of pregnancy. It has been shown to programme cardiac and endothelial dysfunction in the offspring in adult life. However, the mechanisms via which this occurs remain elusive, precluding the identification of potential therapy. Using an integrative approach at the isolated organ, cellular and molecular levels, we tested the hypothesis that oxidative stress in the fetal heart and vasculature underlies the molecular basis via which prenatal hypoxia programmes cardiovascular dysfunction in later life. In a longitudinal study, the effects of maternal treatment of hypoxic (13% O2) pregnancy with an antioxidant on the cardiovascular system of the offspring at the end of gestation and at adulthood were studied. On day 6 of pregnancy, rats (n = 20 per group) were exposed to normoxia or hypoxia ± vitamin C. At gestational day 20, tissues were collected from 1 male fetus per litter per group (n = 10). The remaining 10 litters per group were allowed to deliver. At 4 months, tissues from 1 male adult offspring per litter per group were either perfusion fixed, frozen, or dissected for isolated organ preparations. In the fetus, hypoxic pregnancy promoted aortic thickening with enhanced nitrotyrosine staining and an increase in cardiac HSP70 expression. By adulthood, offspring of hypoxic pregnancy had markedly impaired NO-dependent relaxation in femoral resistance arteries, and increased myocardial contractility with sympathetic dominance. Maternal vitamin C prevented these effects in fetal and adult offspring of hypoxic pregnancy. The data offer insight to mechanism and thereby possible targets for intervention against developmental origins of cardiac and peripheral vascular dysfunction in offspring of risky pregnancy.

Perinatal exposure to chronic hypoxia induces sustained pulmonary hypertension and structural and functional changes in both pulmonary and systemic vascular beds. The aim of this study was to analyze consequences of high-altitude chronic hypoxia during gestation and early after birth in pulmonary and femoral vascular responses in newborn sheep. Lowland (LLNB; 580 m) and highland (HLNB; 3,600 m) newborn lambs were cathetherized under general anesthesia and submitted to acute sustained or stepwise hypoxic episodes. Contractile and dilator responses of isolated pulmonary and femoral small arteries were analyzed in a wire myograph. Under basal conditions, HLNB had a higher pulmonary arterial pressure (PAP; 20.2 +/- 2.4 vs. 13.6 +/- 0.5 mmHg, P < 0.05) and cardiac output (342 +/- 23 vs. 279 +/- 13 ml x min(-1) x kg(-1), P < 0.05) compared with LLNB. In small pulmonary arteries, HLNB showed greater contractile capacity and higher sensitivity to nitric oxide. In small femoral arteries, HLNB had lower maximal contraction than LLNB with higher maximal response and sensitivity to noradrenaline and phenylephrine. In acute superimposed hypoxia, HLNB reached higher PAP and femoral vascular resistance than LLNB. Graded hypoxia showed that average PAP was always higher in HLNB compared with LLNB at any Po2. Newborn lambs from pregnancies at high altitude have stronger pulmonary vascular responses to acute hypoxia associated with higher arterial contractile status. In addition, systemic vascular response to acute hypoxia is increased in high-altitude newborns, associated with higher arterial adrenergic responses. These responses determined in intrauterine life and early after birth could be adaptive to chronic hypoxia in the Andean altiplano.

SUMMARY1. Carotid chemoreceptor activity was detected in each of fourteen halothane or pentobarbitone anaesthetized exteriorized fetal lambs of 90-143 days gestational age.Activity was about 5 Hz at a Pa°, of 25 mmHg and it increased as Pa°2 was reduced, either by compressing the umbilical cord or by reducing the (Flo2) oxygen fraction of the gas used to ventilate the ewe.2. Activity increased briskly when 1-2 ml CO2-saturated saline was injected retrogradely into the lingual artery, but not when saline of pH 7'4 or fetal arterial blood was injected.3. In two fetuses near-term chemoreceptor activity was recorded continuously whilst the umbilical cord was ligated and ventilation with air started. Activity increased 200-500 % as Pa°2 fell, but then fell to below control as Pa,°r ose. We suggest that these changes in activity reflect those occurring naturally at birth.4. No spontaneous chemoreceptor activity could be detected on the day of birth in twelve pentobarbitone anaesthetized lambs delivered vaginally or by Caesarean section at 135-146 days. Single baroreceptor activity could however be recorded in these lambs, and chemoreceptor activity could be elicited by hypercapnia. Spontaneous chemoreceptor activity was detected in six of seven lambs more than 2 days old.5. In eight conscious lambs the steady-state respiratory response to isocapnic hypoxia was variable on the day of birth. In six of these lambs the response was significantly greater by the third day.6. We conclude that the arterial chemoreceptors are active and responsive in the fetus, but quiescent in the lamb on the day of birth when Pa 02 has risen. The hypoxic sensitivity of the chemoreceptors is reset from the fetal to the adult range over the next few days.

Background-Epidemiological 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 Results-Chicken embryos were maintained from 0.3 to 0.9 of the 21-day incubation period under normoxic (21% O 2 ) or hypoxic conditions (15% O 2 ). 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 (21.9Ϯ0.4 versus 25.4Ϯ0.6 g), increased femoral artery norepinephrine (NE) content (78.4Ϯ9.4 versus 57.5Ϯ5.0 pg/mm vessel length), and increased the density of periarterial sympathetic nerve fibers (14.4Ϯ0.7 versus 12.5Ϯ0.6 counts/10 4 m 2 ). Arteries from hypoxic embryos were less sensitive to NE (pD 2 , 5.99Ϯ0.04 versus 6.21Ϯ0.10). In the presence of cocaine, however, differences in sensitivity were no longer present. In the embryonic heart, NE content (156.9Ϯ11.0 versus 108.1Ϯ14.7 pg/mg wet wt) was also increased after chronic hypoxia. Conclusions-In 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. (Circulation.

The present study aimed to characterize the contractile reactivity of the chicken ductus arteriosus (DA) from the last stage of prenatal development and throughout the perinatal period. Isolated DA rings from 15-day, noninternally-pipped 19-day, and externally-pipped 21-day embryos were studied using myograph techniques. On embryonic day 15, the chicken DA did not respond to O 2 (0 to 21%), norepinephrine (NE), or phenylephrine (Phe) but contracted in response to high-K ϩ solution, the inhibitor of voltage-gated channels 4-aminopyridine, U-46619, and endothelin (ET)-1. These responses increased with advancing incubation age. Contractile responses to O 2, NE, and Phe were present in the 19-and 21-day embryo. Oxygen-induced contraction was restricted to the pulmonary side of the DA and was augmented by the nitric oxide synthase inhibitor N -nitro-L-arginine methyl ester and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and reduced by the peptidic ET A and ETB-receptor antagonist PD-142,893. Transmural electrical stimulation of nerves, the nonselective cyclooxygenase (COX) inhibitor indomethacin, the COX-1 inhibitor valeryl salicylate, the COX-2 inhibitor nimesulide, the inhibitor of ATP-sensitive K ϩ channels glibenclamide, and the inhibitor of Ca 2ϩ -activated K ϩ channels tetraethylammonium did not cause contraction of the DA rings at any age. We conclude that transition to ex ovo life is accompanied by dramatic changes in chicken DA reactivity. At 0.7 incubation, excitation-contraction and pharmacomechanical coupling for several contractile agonists are already present, whereas the constrictor effects of O 2 and cathecolamines appear later in development and are located in the pulmonary side of the DA. ductus arteriosus; chicken embryo; potassium channels; oxygen sensing; cathecolamines.THE DUCTUS ARTERIOSUS (DA) is a vessel that connects the pulmonary artery to the aorta and provides, during the fetal life, a pulmonary-to-systemic diversion that shunts more than half of the right ventricle output away from the nonventilated lungs into the systemic circulation (43, 47). The main factors maintaining patency of the DA in utero are low O 2 tension, high levels of circulating PGE 2 , and locally produced PGE 2 and PGI 2 (24, 43). Failure of DA closure after birth is a common complication of premature delivery that is still presenting challenges in terms of diagnosis, assessment, and treatment options (43).Although the isolated DA is sensitive to a wide range of contractile agonists, the major factor actively stimulating contraction at birth is increasing O 2 tension, which has a profound effect on the DA, both directly and by modulating its response to vasodilators and vasoconstrictors (43). To constrict properly after birth, the DA prepares itself for this specific task from a quite early onset during development (3). This preparation is reflected by changes in responsiveness with advancing gestational age. These have been extensively characterized in numerous mammalian specie...