Placental Insufficiency Leads to Development of Hypertension in Growth-Restricted Offspring

Alexander, Barbara T.

doi:10.1161/01.hyp.0000053448.95913.3d

Cited by 265 publications

(325 citation statements)

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“…There was a trend for increased total protein levels in sham rats treated with 5 mg/kg per day ELP‐VEGF, but it is possible that degradation products of the infused protein itself are being detected in this assay. It has been widely studied that the RUPP surgery induces fetal resorption and intrauterine growth restriction of the surviving pups 72, 73, 74, 75, 76. Fetal resorption and fetal growth restriction was observed in our study as well (Table 1 and Figure S3), validating the success of the RUPP procedure in our rats.…”

Section: Resultssupporting

confidence: 87%

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

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Mahdi

Chapman

et al. 2017

JAHA

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BackgroundPreeclampsia is a hypertensive syndrome that complicates 3% to 5% of pregnancies in the United States. Preeclampsia originates from an improperly vascularized and ischemic placenta that releases factors that drive systemic pathophysiology. One of these factors, soluble fms‐like tyrosine kinase‐1, is believed to sequester vascular endothelial growth factor (VEGF), leading to systemic endothelial dysfunction and hypertension. With the goal of targeting soluble fms‐like tyrosine kinase‐1 while simultaneously preventing fetal exposure to VEGF, we fused VEGF to elastin‐like polypeptide, a biopolymer carrier that does not cross the placental barrier (ELP‐VEGF).Methods and Results ELP‐VEGF restored in vitro endothelial cell tube formation in the presence of plasma from placental ischemic rats. Long‐term administered ELP‐VEGF in pregnant rats accumulated in maternal kidneys, aorta, liver, and placenta, but the protein was undetectable in the pups when administered at therapeutic doses in dams. Long‐term administration of ELP‐VEGF in a placental ischemia rat model achieved dose‐dependent attenuation of hypertension, with blood pressure equal to sham controls at a dose of 5 mg/kg per day. ELP‐VEGF infusion increased total plasma soluble fms‐like tyrosine kinase‐1 levels but dramatically reduced free plasma soluble fms‐like tyrosine kinase‐1 and induced urinary excretion of nitrate/nitrite, indicating enhanced renal nitric oxide signaling. ELP‐VEGF at up to 5 mg/kg per day had no deleterious effect on maternal or fetal body weight. However, dose‐dependent adverse events were observed, including ascites production and neovascular tissue encapsulation around the minipump.Conclusions ELP‐VEGF has the potential to treat the preeclampsia maternal syndrome, but careful dosing and optimization of the delivery route are necessary.

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Section: Resultssupporting

confidence: 87%

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

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Mahdi

Chapman

et al. 2017

JAHA

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“…1 Perturbations of the maternal environment that lead to intrauterine growth retardation (IUGR) can have a marked impact on the grown offspring, including increased cardiovascular risk factors (eg, blood pressure and insulin resistance 1,2 ) and reduced adult life span. 3 A wide range of experimental interventions have been used to provoke developmental programming, including disturbances in maternal nutrition (eg, undernutrition and nutritional imbalances 4 ), restriction of uterine blood flow, 5 and the administration of drugs (eg, glucocorticoids 2 and NO synthase inhibitors 6,7 ).…”

mentioning

confidence: 99%

Maternal Endothelial Nitric Oxide Synthase Genotype Influences Offspring Blood Pressure and Activity in Mice

Vliet

Chafe

2007

Hypertension

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Abstract-Deficiencies in maternal endothelial NO synthase (eNOS) have been associated with pregnancy complications, intrauterine growth retardation, and altered vascular function in offspring. In the present study, we investigated the influence of the maternal eNOS genotype on offspring's blood pressure, heart rate, and locomotor activity. The effect of maternal eNOS genotype was made by comparing telemetered blood pressure and activity between 2 groups of 13-to 16-week-old male heterozygous eNOS knockout mice, 1 produced by a cross of eNOS knockout (eNOS Ϫ/Ϫ ) mothers and wild-type (eNOS ϩ/ϩ ) fathers (eNOS ϩ/ϪMAT offspring, Nϭ11), the other by a cross of eNOS ϩ/ϩ mothers and eNOS Ϫ/Ϫ fathers (eNOS ϩ/ϪPAT offspring, Nϭ10). Data were also collected for homozygous eNOS Ϫ/Ϫ and eNOS ϩ/ϩ mice (Nϭ15 each). Heterozygous eNOS knockout mice exhibited blood pressures that were intermediate to the eNOS ϩ/ϩ and eNOS Ϫ/Ϫ groups. Relative to eNOS ϩ/ϪPAT mice, eNOS ϩ/ϪMAT mice exhibited significant increases in nocturnal diastolic arterial pressure and diurnal variations (dark-light difference) in systolic, mean, and diastolic arterial pressure. In addition, indices of spontaneous nocturnal locomotor activity, including both the proportion of time spent active and the intensity of activity when active, were also significantly increased. Heart rate did not differ between the groups. Our results suggest that the maternal eNOS genotype influences both blood pressure and behavior of offspring, possibly as a consequence of developmental programming associated with intrauterine growth retardation. Key Words: experimental hypertension Ⅲ pregnancy Ⅲ developmental programming Ⅲ maternal environment Ⅲ hyperactivity Ⅲ knockout mice Ⅲ telemetry Ⅲ nitric oxide T he characteristics of many physiological systems are influenced by the conditions prevailing during development. 1 Perturbations of the maternal environment that lead to intrauterine growth retardation (IUGR) can have a marked impact on the grown offspring, including increased cardiovascular risk factors (eg, blood pressure and insulin resistance 1,2 ) and reduced adult life span. 3 A wide range of experimental interventions have been used to provoke developmental programming, including disturbances in maternal nutrition (eg, undernutrition and nutritional imbalances 4 ), restriction of uterine blood flow, 5 and the administration of drugs (eg, glucocorticoids 2 and NO synthase inhibitors 6,7 ).A relatively unexplored possibility is that developmental programming could also occur as a consequence of maternal genotype. Maternal endothelial NO synthase (eNOS) is a potential candidate in this regard, because eNOS has been shown to play an important role in the regulation of uterine blood flow, 8,9 and IUGR has been observed in rats treated with inhibitors of NO synthase 6,7 and in mice with targeted deletion of the eNOS gene (eNOS Ϫ/Ϫ ) 8,10 . In humans, polymorphisms of the eNOS gene are common and are associated with endothelial dysfunction, 11-13 increased uterine artery resistan...

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“…Because IUGR within the Western world is more likely the result of reduced uterine perfusion, 24 we have developed a model of fetal programming induced by placental insufficiency caused by hypoxia and fetal undernutrition. 25 Using this model, we previously reported that reduced uterine perfusion initiated at day 14 of gestation in the rat results in growth-restricted offspring that are hypertensive as early as 4 weeks of age. 25 Furthermore, marked elevations in mean arterial pressure (MAP) remain evident in male growth-restricted offspring at 12 weeks of age.…”

mentioning

confidence: 99%

“…25 Using this model, we previously reported that reduced uterine perfusion initiated at day 14 of gestation in the rat results in growth-restricted offspring that are hypertensive as early as 4 weeks of age. 25 Furthermore, marked elevations in mean arterial pressure (MAP) remain evident in male growth-restricted offspring at 12 weeks of age. Because increased renal sympathetic nerve activity appears to be a causal mechanism in primary hypertension, 26 we determined the role of the renal nerves in mediating the hypertension observed in adult male growthrestricted offspring, a product of placental insufficiency.…”

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confidence: 99%

Renal Denervation Abolishes Hypertension in Low-Birth-Weight Offspring From Pregnant Rats With Reduced Uterine Perfusion

et al. 2005

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Abstract-Low birth weight is a risk factor for the subsequent development of hypertension in humans. We previously reported that reduced uterine perfusion in the pregnant rat results in growth-restricted offspring predisposed to the development of hypertension. The purpose of this study was to determine whether the sympathetic nervous system plays a role in mediating hypertension in this model of low birth weight. Key Words: hypertension, pregnancy Ⅲ rats Ⅲ renal nerves Ⅲ denervation Ⅲ sympathetic nervous system H ypertension is a multifactorial disorder thought to result from both genetic and environmental factor interactions. Recent epidemiological studies 1,2 suggest that a predisposition for development of hypertension may be programmed by factors initiated in utero, 3 an observation supported by many animal studies. 4 -7 Fetal malnutrition limits fetal growth and results in small-for-gestational-age newborns. 8,9 Findings from both epidemiological and animal studies suggest that fetal malnutrition may also program or permanently alter fetal structure and physiology, resulting in an increased risk for development of hypertension and cardiovascular disease. 3,10 -12 However, the mechanisms mediating low birth weight (LBW) and hypertension remain to be elucidated.In humans, few studies have examined the relationship between the sympathetic nervous system (SNS) and LBW, and controversy exists with regards to whether LBW individuals are associated with increases [13][14][15] or decreases in sympathetic activity. 16 Evidence for alterations in the SNS is noted in some animal models of intrauterine growth restriction (IUGR), because plasma levels of circulating catecholamines are increased. [17][18][19][20][21] This observation has been noted in growth-restricted offspring from pregnant rats fed a proteinrestricted diet during gestation, 17 in a naturally occurring model of IUGR using piglets, 18,19 and in a model of IUGR induced by placental insufficiency in the rat 20 and in sheep. 21 Additionally, hypoxia during fetal development leads to increased sympathetic innervation. 22,23 However, no further assessment of the SNS in association with IUGR has been examined.Nutrient and oxygen supply limitations are the components of the intrauterine environment that limit fetal growth and result in small-for-gestational-age newborns. Because IUGR within the Western world is more likely the result of reduced uterine perfusion, 24 we have developed a model of fetal programming induced by placental insufficiency caused by hypoxia and fetal undernutrition. 25 Using this model, we previously reported that reduced uterine perfusion initiated at day 14 of gestation in the rat results in growth-restricted offspring that are hypertensive as early as 4 weeks of age. 25 Furthermore, marked elevations in mean arterial pressure (MAP) remain evident in male growth-restricted offspring at 12 weeks of age. Because increased renal sympathetic nerve activity appears to be a causal mechanism in primary hypertension, 26 we determined the ro...

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Placental Insufficiency Leads to Development of Hypertension in Growth-Restricted Offspring

Cited by 265 publications

References 35 publications

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

Maternal Endothelial Nitric Oxide Synthase Genotype Influences Offspring Blood Pressure and Activity in Mice

Renal Denervation Abolishes Hypertension in Low-Birth-Weight Offspring From Pregnant Rats With Reduced Uterine Perfusion

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