Intrauterine growth restriction programs an accelerated age-related increase in cardiovascular risk in male offspring

Dasinger, John Henry; Intapad, Suttira; Backstrom, Miles A; Carter, Anthony J.; Alexander, Barbara T.

doi:10.1152/ajprenal.00123.2016

Cited by 20 publications

(14 citation statements)

References 45 publications

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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%

“…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. There were no differences in total litter size among the treatment groups, but all RUPP-treated rats had more resorbed fetuses than sham-treated rats did (Table 1 and Figure S3).…”

Section: Other Effects Of Elp-vegf Treatment In Pregnant Ratssupporting

confidence: 88%

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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%

Section: Other Effects Of Elp-vegf Treatment In Pregnant Ratssupporting

confidence: 88%

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

Logue

Mahdi

Chapman

et al. 2017

JAHA

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“…We previously reported that circulating levels of testosterone are significantly elevated in mIUGR relative to age-matched control in young adulthood [ 22 ] but no longer differ by 12 months of age [ 23 ]. To determine if changes in testosterone correlate with altered glucose homeostasis, we performed an oral glucose tolerance test 6 weeks after sham, castration, or castration with testosterone replacement.…”

Section: Resultsmentioning

confidence: 99%

“…Castration abolishes the increase in blood pressure in mIUGR [ 22 ] indicating the permissive role of testosterone in the etiology of increased cardiovascular risk originating in early life. However, in later life testosterone associated blood pressure does not remain elevated in mIUGR relative to their normal birth weight counterparts [ 23 ]. Whether IUGR programs impaired glucose homeostasis in mIUGR, and whether a decrease in endogenous testosterone plays a role in the development of this impairment are unknown.…”

Section: Introductionmentioning

confidence: 99%

Testosterone is protective against impaired glucose metabolism in male intrauterine growth-restricted offspring

et al. 2017

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Placental insufficiency alters the intrauterine environment leading to increased risk for chronic disease including impaired glucose metabolism in low birth weight infants. Using a rat model of low birth weight, we previously reported that placental insufficiency induces a significant increase in circulating testosterone in male intrauterine growth-restricted offspring (mIUGR) in early adulthood that is lost by 12 months of age. Numerous studies indicate testosterone has a positive effect on glucose metabolism in men. Female growth-restricted littermates exhibit glucose intolerance at 6 months of age. Thus, the aim of this paper was to determine whether mIUGR develop impaired glucose metabolism, and whether a decrease in elevated testosterone levels plays a role in its onset. Male growth-restricted offspring were studied at 6 and 12 months of age. No impairment in glucose tolerance was observed at 6 months of age when mIUGR exhibited a 2-fold higher testosterone level compared to age-matched control. Fasting blood glucose was significantly higher and glucose tolerance was impaired with a significant decrease in circulating testosterone in mIUGR at 12 compared with 6 months of age. Castration did not additionally impair fasting blood glucose or glucose tolerance in mIUGR at 12 months of age, but fasting blood glucose was significantly elevated in castrated controls. Restoration of elevated testosterone levels significantly reduced fasting blood glucose and improved glucose tolerance in mIUGR. Thus, our findings suggest that the endogenous increase in circulating testosterone in mIUGR is protective against impaired glucose homeostasis.

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“…In each of these models, progeny are lighter at birth but catch up in body weight to that of controls during or before adulthood. 37,[41][42][43][44][45][46][47][48][49][50][51] Development of obesity is variable, with obesity reported in adult female, but not male, RUPP rats with ageing, 52,53 but normal body and central fat abundance in adult progeny of sFlt1-transduced mice of both sexes. 54 Likewise, effects of in utero exposure to a preeclamptic phenotype on postnatal glucose tolerance are sex-and agedependent in the RUPP rat, 53,55 L-NAME-treated rat 56 and sFlt1-transduced mice 51 models of PE.…”

Section: Developmental Programming Of Cvd Risk By In Utero Exposure Tmentioning

confidence: 99%

Mechanisms linking exposure to preeclampsia in utero and the risk for cardiovascular disease

Gatford

Care

Bianco‐Miotto

et al. 2020

J Dev Orig Health Dis

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Preeclampsia (PE) is now recognised as a cardiovascular risk factor for women. Emerging evidence suggests that children exposed to PE in utero may also be at increased risk of cardiovascular disease (CVD) in later life. Individuals exposed to PE in utero have higher systolic and diastolic blood pressure and higher body mass index (BMI) compared to those not exposed to PE in utero. The aim of this review is to discuss the potential mechanisms driving the relationship between PE and offspring CVD. Exposure to an adverse intrauterine environment as a consequence of the pathophysiological changes that occur during a pregnancy complicated by PE is proposed as one mechanism that programs the fetus for future CVD risk. Consistent with this hypothesis, animal models of PE where progeny have been studied demonstrate causality for programming of offspring cardiovascular health by the preeclamptic environment. Shared alleles between mother and offspring, and shared lifestyle factors between mother and offspring provide alternate pathways explaining associations between PE and offspring CVD risk. In addition, adverse lifestyle habits can also act as second hits for those programmed for increased CVD risk. PE and CVD are both multifactorial diseases and, hence, identifying the relative contribution of PE to offspring risk for CVD is a very complex task. However, considering the emerging strong association between PE and CVD, those exposed to PE in utero may benefit from targeted primary CVD preventive strategies.

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Intrauterine growth restriction programs an accelerated age-related increase in cardiovascular risk in male offspring

Cited by 20 publications

References 45 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

Testosterone is protective against impaired glucose metabolism in male intrauterine growth-restricted offspring

Mechanisms linking exposure to preeclampsia in utero and the risk for cardiovascular disease

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