Hypoxia-induced Growth Research Articles

Regulatory role of sphingomyelin metabolites in hypoxia-induced vascular smooth muscle cell proliferation.

Vascular cell adaptive response to hypoxic stress includes enhanced production of sphingomyelin metabolites that regulate cell growth. Here, we examined the vascular smooth muscle (VSM) cell adaptive response to hypoxia (2 and 5% O(2)) and demonstrated that acute (</=16h) hypoxic stress significantly stimulated VSM cell growth compared to cells grown under normoxic (21% O(2)) conditions. This stimulatory effect of hypoxia on VSM cell growth was significantly inhibited by pretreatment of cells with D-erythro-N,N-dimethylsphingosine, an inhibitor of sphingosine kinase. These results suggest a mechanism by which sphingosine 1-phosphate (S-1-P), a promitogenic sphingolipid-derived second messenger, may play a key role in hypoxia-induced VSM cell growth. Supporting this, S-1-P formation was significantly increased in VSM cells subjected to hypoxia. The hypoxia-induced increase in S-1-P level correlated with the decrease in total cellular ceramide content, a sphingolipid metabolite associated with inhibition of cell growth. The activity of sphingomyelinase was also significantly inhibited in hypoxia-treated VSM cells, likely further contributing to a decrease in total intracellular content of ceramide. As a decrease in ceramide content may play a role in hypoxia-induced VSM growth, we next examined the effects of ceramide in VSM cell growth. Elevating intracellular ceramide content through exogenous (C(6)-ceramide) or endogenous (ceramidase inhibition) manipulations led to a decrease in hypoxia-induced VSM cell growth. In contrast, hypoxia-induced VSM cell growth was further enhanced by S-1-P treatment. Together, our study indicates that hypoxia-induced VSM cell growth may be modulated by sphingomyelin metabolism that results in reduction of total intracellular ceramide level with concomitant increase in S-1-P formation.

Hypoxia Stimulates p16 Expression and Association with cdk4

Exposure of CV-1P cells to hypoxic conditions causes cell proliferation inhibition concomitant with the accumulation of pRb in the hypophosphorylated, growth suppressive form. This is in part due to inhibition of pRb-directed cdk4 and cdk2 activity. In this study we attempted to elucidate the mechanism by which cdk4 is inactivated under hypoxic conditions. After 18 h of hypoxia, CV-1P cells are inhibited from progressing from G1 phase into the S phase of the cell cycle. This occurs in conjunction with dephosphorylation of serine-795, which is a putative substrate of cdk4. The amounts of cdk4, cdk6, and the D type cyclins are not affected by 18 h of hypoxia. The levels of cdki p16, p18, p19, and p57 under aerobic or hypoxic conditions were analyzed and although the levels of most cdki are unaffected by hypoxic conditions, the level of p16 increases significantly by 18 h of hypoxia. The mechanism by which cdk4 activity is inhibited under hypoxic conditions may be mediated through p16 association with cdk4. Immunoprecipitation analysis shows that p16 binds to cdk4 under hypoxic conditions but does not in cells maintained under aerobic conditions. Thus p16 may be involved in hypoxia-induced growth inhibition.

Hypoxia links ATR and p53 through replication arrest.

Previous studies have demonstrated that phosphorylation of human p53 on serine 15 contributes to protein stabilization after DNA damage and that this is mediated by the ATM family of kinases. However, cellular exposure to hypoxia does not induce any detectable level of DNA lesions compared to ionizing radiation, and the oxygen dependency of p53 protein accumulation differs from that of HIF-1, the hypoxia-inducible transcription factor. Here we show that, under severe hypoxic conditions, p53 protein accumulates only in S phase and this accumulation correlates with replication arrest. Inhibition of ATR kinase activity substantially reduces hypoxia-induced phosphorylation of p53 protein on serine 15 as well as p53 protein accumulation. Thus, hypoxia-induced cell growth arrest is tightly linked to an ATR-signaling pathway that is required for p53 modification and accumulation. These studies indicate that the ATR kinase plays an important role during tumor development in responding to hypoxia-induced replication arrest, and hypoxic conditions could select for the loss of key components of ATR-dependent checkpoint controls.

Hypoxia-induced Proliferative Response of Vascular Adventitial Fibroblasts Is Dependent on G Protein-mediated Activation of Mitogen-activated Protein Kinases

Hypoxia has been shown to act as a proliferative stimulus for adventitial fibroblasts of the pulmonary artery. The signaling pathways involved in this growth response, however, remain unclear. We tested the hypothesis that hypoxia-induced proliferation of fibroblasts would be dependent on distinct (compared with serum) activation and utilization patterns of mitogen-activated protein (MAP) kinases initiated by Galpha(i/o) proteins. We found that hypoxia stimulated increases in DNA synthesis and growth of quiescent fibroblasts in the absence of exogenous mitogens and also markedly augmented serum-stimulated growth responses. Hypoxia caused a transient activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), the time course and pattern of which was somewhat similar to that induced by serum but which was of lesser magnitude. On the other hand, hypoxia-induced activation of p38 MAP kinase was biphasic, whereas serum-stimulated activation of p38 MAP kinase was transient, and the magnitude of activation was greater for hypoxia compared with that of serum stimulation. ERK1/2, JNK1, and p38 MAP kinase but not JNK2 were necessary for hypoxia-induced proliferation because PD98059, SB202190, and JNK1 antisense oligonucleotides nearly ablated the growth response. JNK2 appeared to act as a negative modulator of hypoxia-induced growth because JNK2 antisense oligonucleotides led to an increase in DNA synthesis. In serum-stimulated cells, antisense JNK1 oligonucleotides and PD98059 had inhibitory effects on proliferation, whereas SB202190 led to an increase in DNA synthesis. Pertussis toxin, which blocks Galpha(i/o)-mediated signaling, markedly attenuated hypoxia-induced DNA synthesis and activation of ERK and JNK but not p38 MAP kinase. We conclude that hypoxia itself can act as a growth promoting stimulus for subsets of bovine neonatal adventitial fibroblasts largely through Galpha(i/o)-mediated activation of a complex network of MAP kinases whose specific contributions to hypoxia-induced proliferation differ from traditional serum-induced growth signals.

Mechanisms of chronic hypoxia-induced renal cell growth

Chronic local tissue hypoxia appears to play an important role in the initiation and progression of chronic renal disease. We examined the effect of local hypoxia on cultured renal tubular epithelial and mesangial cell proliferation, dedifferentiation, and extracellular matrix synthesis. The underlying signaling mechanisms whereby hypoxia induces renal cell growth were evaluated. The roles of protein kinase C, p38 mitogen-activated protein kinase, TGF-beta1, osteopontin, and nitric oxide were determined.

Dietary l-arginine prevents fetal growth restriction in rats

Alterations in maternal plasma arginine concentration accompany normal pregnancy. Nitric oxide is synthesized from L-arginine and influences fetal growth. We hypothesized that L-arginine would influence fetal growth and hypoxia-induced uricemia in a maternal hypoxia-induced fetal growth restriction model. Fetal growth on day 21 of gestation was assessed in timed pregnant Wistar rats with or without exposure to maternal hypobaric hypoxia. Animals exposed to hypoxia received either no supplement or supplementation of drinking water with 0.2% L-arginine, 2% L-arginine, or 2% glycine. On day 21 of gestation, fetuses were delivered by hysterotomy and fetal and placental weights were obtained. Maternal and fetal plasma were assayed for uric acid as an index of tissue hypoxia. Xanthine oxidase and xanthine dehydrogenase, precursors of uric acid and reactive oxygen species, were assayed in maternal tissue. Results were analyzed by analysis of variance with correction for multiple comparisons. Exposure of rats on normal diets to hypoxia resulted in a 30% reduction in fetal weights. L-Arginine, 2% or 0.2%, prevented the reduction in fetal weight (p < 0.0001). Isocaloric and isonitrogenous supplementation with glycine did not influence hypoxia-induced fetal growth restriction. L-Arginine, but not glycine, ameliorates maternal hypoxia-induced fetal growth restriction in the rat.

Endothelin receptor A antagonism prevents hypoxia-induced intrauterine growth restriction in the rat

OBJECTIVE: Our purpose was to investigate the hypothesis that endothelin plays a critical role in maternal hypoxia-induced intrauterine growth restriction. STUDY DESIGN: Chronic indwelling venous and arterial catheters were placed on day 17 of a 22-day gestation in timed-pregnant Sprague-Dawley rats. Twelve rats were infused with saline solution and 12 with 6 mg/kg per day FR139317, an endothelin receptor A–specific antagonist. For gestational days 18 to 21 half the rats in each infusion group were housed in a normoxic environment and the other half in a hypoxic (14% oxygen) environment. On day 21 an arterial blood gas level was determined, the rats were then anesthetized, and a hysterotomy was performed. The weight of each pup and its corresponding placenta was recorded. Statistical significance was determined by analysis of variance. RESULTS: Among the rats receiving saline solution infusions, fetal weights were 20% less and placental weights were 11% less for those housed in a hypoxic environment compared with those housed in a normoxic environment (p < 0.003). Among the rats receiving FR139317 infusions, fetal and placental weights were not significantly different for those in a hypoxic environment compared with those in a normoxic environment. The fetal and placental weights for the rats receiving FR139317 infusion in hypoxic or normoxic environments were similar to those receiving saline solution in a normoxic environment. CONCLUSIONS: Endothelin plays a critical role in hypoxia-induced intrauterine growth restriction. Infusion of an endothelin antagonist prevents the intrauterine growth restriction caused by chronic hypoxia. (Am J Obstet Gynecol 1997;176:73-6.)

Endothelin subtype a receptor antagonism normalizes hypoxia-induced intrauterine growth restriction.

Endothelin subtype a receptor antagonism normalizes hypoxia-induced intrauterine growth restriction.

Postnatal development of hippocampal and neocortical cholinergic and serotonergic innervation in rat: Effects of nitrite-induced prenatal hypoxia and nimodipine treatment

Postnatal development of ingrowing cholinergic and serotonergic fiber patterns were studied in the rat hippocampus and parietal cortex employing a histochemical procedure for acetylcholinesterase as a cholinergic fiber marker, and immunocytochemistry of serotonin for serotonergic fiber staining. The rat pups were killed at postnatal days 1, 3, 5, 7, 10, and 20. The development of cholinergic and serotonergic innervation was described and the fiber density quantified under normal conditions and after long-term prenatal anemic hypoxia induced by chronic exposure to sodium nitrite. Furthermore, a third group was studied in which the nitrite hypoxia was combined with a simultaneous treatment with the Ca 2+ entry blocker nimodipine to test the neuroprotective potential of this drug. Quantitative measurement of fiber density from postnatal day 1 to day 20 yielded the following results: (i) both neurotransmitter systems revealed an age-dependent and an anatomically-organized developmental pattern; (ii) the serotonergic innervation of the dorsal hippocampus preceded that of cholinergic afferentation in postnatal days 1–3; (iii) prenatal hypoxia induced a transient delay in the innervation of parietal neocortex and dentate gyrus for both neurotransmitter systems, but left the innervation of the cornu ammonis unaffected; and (iv) the hypoxia-induced retardation of cholinergic and serotonergic fiber development was prevented by concomitant application of the Ca 2+ -antagonist nimodipine during the hypoxia. The results indicate that prenatal hypoxia evokes a temporary delay in the cholinergic and serotonergic fiber outgrowth in cortical target areas in a region-specific manner. The hypoxia-induced growth inhibition is prevented by the calcium antagonist nimodipine, which supports the importance of the intracellular Ca 2+ homeostasis of cells and growth cones in regulating axonal proliferation.

Hypobaric hypoxia-induced intrauterine growth retardation.

2-week-pregnant New Zealand White rabbits were placed into a hypobaric chamber and maintained at 3,657 m (12,000 ft). Upon delivery (31 +/- 1 days) or at cesarean section (on day 30), all newborns were sacrificed and organ weights were compared to those of control pups maintained at 128 m (420 ft). Significant findings in the hypobaric animals included a diminished birth weight, placental weight, and liver weight per body weight. Placental weight per body weight was similar in both groups. The brain weight per body weight, brain to liver ratio, and right ventricle to left ventricle plus intraventricular septal weight ratio were significantly increased in the hypobaric pups.

Hypoxia and malnutrition in newborn rats: effects on RNA, DNA, and protein in tissues.

ARTICLESHypoxia and malnutrition in newborn rats: effects on RNA, DNA, and protein in tissuesDB Cheek, JE Graystone, and RD RoweDB Cheek, JE Graystone, and RD RowePublished Online:01 Sep 1969https://doi.org/10.1152/ajplegacy.1969.217.3.642MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByObservations on obesity patterns in tetralogy of Fallot patients from childhood to adulthood22 September 2016 | Cardiology in the Young, Vol. 27, No. 5Endocranial and masticatory muscle volumes in myostatin-deficient mice1 December 2014 | Royal Society Open Science, Vol. 1, No. 4Upper airway loading induces growth retardation and change in local chondrocyte IGF-I expression is reversed by stimulation of GH release in juvenile ratsYael Segev, Nilly Berdugo-Boura, Orit Porati, and Ariel Tarasiuk1 November 2008 | Journal of Applied Physiology, Vol. 105, No. 5Morphometric Evaluation of Changes in Lung Structure Due to High Altitude27 May 2008Chronic upper airway resistive loading induces growth retardation via the GH/IGF-I axis in prepubescent ratsAriel Tarasiuk, and Yael Segev1 March 2007 | Journal of Applied Physiology, Vol. 102, No. 3Effects of exposure to a simulated altitude of 5500 m on energy metabolic pathways in ratsRespiratory Physiology & Neurobiology, Vol. 141, No. 1Effect of growth hormone therapy in mitigating hypoxia-induced and food restriction-induced growth retardation in the newborn ratCritical Care Medicine, Vol. 27, No. 10Treatment of children with congenital heart disease and growth retardation with recombinant human growth hormoneActa Paediatrica, Vol. 85, No. 2Growth and congenital heart disease10 March 2008 | Journal of Paediatrics and Child Health, Vol. 29, No. 2The control of cell mass and replication. The DNA unit - a personal 20-year studyEarly Human Development, Vol. 12, No. 3The effect of perinatal anoxia on amino acid metabolism in the developing brain. Part I: The effect of experimental anoxia on the free amino acid patterns in the brain of neonatal ratsBrain and Development, Vol. 7, No. 4Growth of lowland native children of European Ancestry during sojourn at high altitude (3,200 m)American Journal of Physical Anthropology, Vol. 61, No. 2Effect of hypoxia on nucleic acid and protein synthesis in different brain regionsNeurochemical Research, Vol. 6, No. 5Factors which influence the timing of maximum growth rate of the head in low birthweight infants.Archives of Disease in Childhood, Vol. 52, No. 2Toxic Effects of Elevated Oxygen Tension on Brain MaturationToxic Effects of Elevated Oxygen Tension on Brain MaturationEffect of adaptation to high-altitude hypoxia in early ontogeny on higher nervous activityBulletin of Experimental Biology and Medicine, Vol. 82, No. 2Nasoesophageal Intubation in the Pierre Robin Syndrome2 July 2016 | Clinical Pediatrics, Vol. 15, No. 2Maturation of the Mammalian Nervous System and the Ontogeny of BehaviorGrowth and development after cardiovascular surgery in infants and childrenProgress in Cardiovascular Diseases, Vol. 18, No. 1Effects of Interference with Cerebellar Maturation on the Development of Locomotion. An Experimental Model of Neurobehavioral RetardationAstrocytosis without globules in infant cerebral white matterJournal of the Neurological Sciences, Vol. 22, No. 3Clinical Review : Pediatric and Otologic Aspects of Clinical Research in Cleft Palate2 July 2016 | Clinical Pediatrics, Vol. 13, No. 7Recovery of rat brain from a brief hyperphenylalaninemic insult early in developmentBrain Research, Vol. 73, No. 1NEONATAL UNDERNUTRITION AND RNA SYNTHESIS IN DEVELOPING RAT BRAINJournal of Neurochemistry, Vol. 22, No. 4COMPARATIVE EFFECTS OF HYPOTHYROIDISM, HYPERTHYROIDISM AND UNDERNUTRITION ON THE PROTEIN AND NUCLEIC ACID CONTENTS OF THE CEREBELLUM IN THE YOUNG RATJournal of Neurochemistry, Vol. 21, No. 4CEREBELLAR DEVELOPMENT IN THE RAT AFTER EARLY POSTNATAL DAMAGE BY METHYLAZOXY-METHANOL: DNA, RNA AND PROTEIN DURING RECOVERYJournal of Neurochemistry, Vol. 21, No. 3Effects of different schedules of early undernutrition on the preweaning growth of the rat cerebellumExperimental Neurology, Vol. 38, No. 3Effects of two levels of gastational-lactational undernutrition on the postweaning growth of the rat cerebellumExperimental Neurology, Vol. 38, No. 3The influence of nutrition on neural and behavioral development. IV. Effects of infantile undernutrition on the growth of the cerebellumDevelopmental Psychobiology, Vol. 5, No. 2IMPAIRMENT OF GROWTH AND DEVELOPMENT OF THE RAT BRAIN BY HYPEROXIA AT ATMOSPHERIC PRESSUREJournal of Neurochemistry, Vol. 19, No. 1Influence of Dietary Protein on Rat Skeletal Muscle GrowthThe Journal of Nutrition, Vol. 102, No. 1Morphometric estimation of pulmonary diffusion capacityRespiration Physiology, Vol. 11, No. 2THE EFFECTS OF UNDERNUTRITION UPON THE ENERGY RESERVE OF THE BRAIN AND UPON OTHER SELECTED METABOLIC INTERMEDIATES IN BRAINS AND LIVERS OF INFANT RATSJournal of Neurochemistry, Vol. 18, No. 1The influence of nutrition on neural and behavioral development. I. Critical review of some data on the growth of the body and the brain following dietary deprivation during gestation and lactationDevelopmental Psychobiology, Vol. 3, No. 4 More from this issue > Volume 217Issue 3September 1969Pages 642-645 Copyright & PermissionsCopyright © 1969 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1969.217.3.642PubMed5807686History Published online 1 September 1969 Published in print 1 September 1969 Metrics