Effects of hypoxia-induced intrauterine growth restriction on cardiopulmonary structure and function during adulthood

Rueda-Clausen, Christian F.; Morton, Jude S.; Davidge, Sandra T.

doi:10.1093/cvr/cvn341

Cited by 157 publications

(166 citation statements)

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“…The gene expression of p53 is increased in severe hypoxia (Li et al 1994;An et al 1998;Hammond et al 2002;Fan et al 2009). In addition, severe hypoxia induces IUGR and abortion (Rueda-Clausen et al 2009). However, in our study, IUGR and abortion were not induced by maternal undernutrition.…”

Section: Discussionmentioning

confidence: 99%

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

Ito

Funamoto

Sato

et al. 2012

Tohoku J. Exp. Med.

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Maternal undernutrition during pregnancy is a risk factor for cerebrovascular and cardiovascular diseases in adulthood. Hypoxia-inducible factor 1 alpha (HIF1α) plays an essential role in cellular hypoxic responses, and its increased expression is associated with cerebrovascular and cardiovascular diseases. However, it is not known whether maternal undernutrition influences HIF1α expression in the fetal brain. We therefore analyzed the expression levels of HIF1α and its downstream genes in the fetal brain (day 17.5 of gestation, 1-2 days before birth). Maternal undernutrition did not noticeably affect the fetal body and brain weights. Both HIF1α mRNA and protein levels were increased in the brain under maternal undernutrition, despite the absence of hypoxia, as judged by the staining profile with hypoxyprobe-1 that identifies hypoxic cells. Importantly, maternal undernutrition caused the accumulation of HIF1α protein in oligodendrocyte precursor cells at the subventricular zone, a site of neurogenesis in the fetal brain. Maternal undernutrition also increased the mRNA level of mammalian target of rapamycin (mTOR), which could increase the level of HIF1α protein under normoxia. Furthermore, microarray analysis revealed that expression levels of mRNAs for 10 HIF1α downstream targets, including enolase 1 and hexokinase 1, were increased in the fetal brain under maternal undernutrition. Thus, the biochemical consequence of maternal undernutrition is similar to that of mild hypoxia. In conclusion, maternal undernutrition induces the expression of HIF1α in oligodendrocyte precursor cells at the subventricular zone, and it also induces the expression of hypoxia-related genes in the fetal brain probably via activation of the mTOR pathway.Keywords: fetal brain; hypoxia-inducible factor 1 alpha; hypoxic responses; mammalian target of rapamycin; maternal undernutrition Tohoku J. Exp. Med., 2012, 226 (1), 37-44.

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Section: Discussionmentioning

confidence: 99%

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

Ito

Funamoto

Sato

et al. 2012

Tohoku J. Exp. Med.

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“…Additionally, blood pressure measurements were performed using aortic cannulas at a relatively young age of 4 months compared to 12 months of age in this thesis. Previously, progressive signs of cardiovascular dysfunction have been reported in rat offspring exposed to prenatal hypoxia, with diastolic dysfunction and pulmonary hypertension emerging between 4 and 12 months of age (Rueda-Clausen et al, 2008). We observed no signs of renal injury in hypoxia-exposed offspring at 4 months of age despite significant pathology present at 12 months, which suggest that ageing is an additional stressor in animals exposed to prenatal…”

Section: Elevated Mean Arterial Pressuresupporting

confidence: 63%

“…In 12-month-old offspring, we observed that prenatal hypoxia increased interstitial cardiac fibrosis in both sexes. Pathological myocardial fibrosis is associated with diastolic dysfunction, and although we did not perform echocardiography in our study, a similar model of prenatal hypoxia (12% oxygen, E15 -birth) showed rat offspring had normal cardiac function at 4 months of age but went on to develop left ventricular diastolic dysfunction and increased ventricular collagen expression by 12 months (Rueda-Clausen et al, 2008). This supports our findings in the mouse, and suggests our hypoxia-exposed animals with elevated diastolic blood pressure may be at risk of diastolic dysfunction and therefore heart failure.…”

Section: Increased Cardiac Fibrosis With Prenatal Hypoxia and High Saltmentioning

confidence: 72%

“…Diastolic dysfunction and associated pathological myocardial fibrosis is another common feature in adult rats exposed to hypoxia in utero (Xu et al, 2006;Rueda-Clausen et al, 2008). Interestingly, assessment of blood pressure in rodents using radiotelemetry, the gold standard of blood pressure measurement, has not yet been performed in a model of prenatal hypoxia.…”

Section: Effects Of Prenatal Hypoxia On the Heartmentioning

confidence: 99%

“…Alterations to vascular structure have also been highlighted as partial contributors to perturbed haemodynamic regulation in hypoxia-exposed animals (Rouwet et al, 2002;Rueda-Clausen et al, 2008;. Particularly, the vascular endothelium is susceptible to programming with a strong association observed between low birth weight babies and endothelial dysfunction in young adult life (Leeson et al, 2001).…”

Section: Effects Of Prenatal Hypoxia On the Vasculaturementioning

confidence: 99%

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Gestational hypoxia and programming of disease

Walton¹

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Fetal hypoxia remains the most common complication throughout pregnancy and has a wide aetiology including, but not limited to, placental insufficiency, high altitude living and maternal factors such as smoking and pulmonary disease. Intrauterine growth restriction and subsequent low birth weight are common features of pregnancies complicated by reduced oxygenation. Suboptimal organ development may arise, thereby substantially increasing vulnerability to cardiovascular and renal diseases in adulthood. Recently it has been established that prenatally programmed vulnerability to disease may be exacerbated by a postnatal 'second-hit', such as a high salt diet or ageing. The primary aim of this thesis was to investigate the effects of maternal hypoxia on the programming of cardiovascular and renal disease in mice, and secondly whether excess dietary salt intake throughout life may exacerbate disease outcomes.Pregnant CD1 mice were housed in a hypoxia chamber set to 12% oxygen throughout the last five days of pregnancy, from embryonic day (E) 14.5 until birth (P0). Control animals remained in normoxic room conditions (21% oxygen) throughout pregnancy. Upon littering, animals were removed from the hypoxia chamber and raised in normoxic room conditions. A subset of mice was fed a high salt diet from 10 weeks of age until post-mortem. Mice were housed in metabolic cages for 24 hours to assess renal function under basal conditions, and in response to a 24 hour water deprivation challenge, at 4 and 12 months of age. Blood pressure and microvascular function and structure were assessed in offspring at 12 months of age.Kidneys, hearts and aortas were collected for stereological and histological analyses.Prenatal hypoxia reduced nephron number in the kidneys of male offspring, leading to glomerular hypertrophy, renal fibrosis and mild albuminuria by 12 months of age. However, female offspring exposed to the same hypoxic insult in utero presented with normal number of glomeruli and renal pathology equivalent to control animals by 12 months of age. Both male and female hypoxia-exposed offspring had elevated mean arterial pressure at 12 months of age. A high salt diet throughout adult life increased cardiac tissue fibrosis, particularly in male hypoxia-exposed offspring, and exacerbated renal pathology in male hypoxia-exposed offspring only. Pressurized myography was performed at the time of post-mortem to assess functional, structural and mechanical properties of mesenteric resistance arteries at 12 months of age. Both male and female offspring exposed to maternal hypoxia had significantly 3 impaired endothelial function, which was not exacerbated by the high salt diet. The combination of prenatal hypoxia and a postnatal high salt diet caused marked stiffening of the microvasculature as well as loss of elastin integrity and increased collagen content in the aorta, consistent with vascular stiffness. This suggests that kidneys from female offspring are somehow protected from the in utero insult; however, this protection...

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Growth plasticity of the embryonic and fetal heart

Drenckhahn

2009

BioEssays

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The developing mammalian heart responds to a variety of conditions, including changes in nutrient availability, blood oxygenation, hemodynamics, or tissue homeostasis, with impressive growth plasticity. This ensures the formation of a functional and normal sized organ by birth. During embryonic and fetal development the heart is exposed to various physiological and potentially pathological changes in the intrauterine environment which dramatically impact on normal cardiac function, tissue composition, and morphology. This paper summarizes the mechanisms employed by the embryonic and fetal heart to adapt to various intrauterine challenges to prevent or minimize postnatal consequences of impaired cardiac development. Future investigations of this growth plasticity might lead to new therapeutic strategies for the prevention of cardiac disease in postnatal life.

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Effects of hypoxia-induced intrauterine growth restriction on cardiopulmonary structure and function during adulthood

Abstract: Our study demonstrated that hypoxia-induced IUGR is associated with the development of chronic cardiopulmonary dysfunction during ageing. The implication of these findings is the potential usefulness of neonatal diagnosis as a predictor of cardiopulmonary outcomes during adulthood.

Cited by 157 publications

References 31 publications

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

Gestational hypoxia and programming of disease

Growth plasticity of the embryonic and fetal heart

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