Low-Protein Diet-Induced Fetal Growth Restriction Leads to Exaggerated Proliferative Response to Vascular Injury in Postnatal Life

Background: Maternal malnutrition can lead to fetal growth restriction. This is often associated with organ sparing and long-lasting physiological dysfunctions during adulthood, although the underlying mechanisms are not yet well understood. Methods: Low protein (LP) dietary models in C57BL/6J mice were used to investigate the proximal effects of maternal malnutrition on fetal organ weights and organ sparing at embryonic day 18.5 (E18.5). Results: Maternal 8% LP diet induced strikingly different degrees of fetal growth restriction in different animal facilities, but adjustment of dietary protein content allowed similar fetal body masses to be obtained. A maternal LP diet that restricted fetal body mass by 40% did not decrease fetal brain mass to the same extent, reflecting positive growth sparing of this organ. Under these conditions, fetal pancreas and liver mass decreased by 60-70%, indicative of negative organ sparing. A series of dietary swaps between LP and standard diets showed that the liver is capable of efficient catch-up growth from as late as E14.5 whereas, after E10.5, the pancreas is not. Conclusions: This study highlights that the reproducibility of LP fetal growth restriction studies between laboratories can be improved by careful calibration of maternal dietary protein content. LP diets that induce 30-40% restriction of prenatal growth provide a good model for fetal organ sparing. For the liver, recovery of growth following protein restriction is efficient throughout fetal development but, for the pancreas, transient LP exposures spanning the progenitor expansion phase lead to an irreversible fetal growth deficit.

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Periconception maternal low-protein diet adversely affects male mouse fetal bone growth and mineral density quality in late gestation

Journal of Developmental Origins of Health and Disease ◽

10.1017/s204017442000046x ◽

2020 ◽

pp. 1-12

Author(s):

Stuart A. Lanham ◽

Stephanie J. Smith ◽

Adam J. Watkins ◽

Emma S. Lucas ◽

Niamh MacCaoilte ◽

...

Keyword(s):

Bone Formation ◽

Fetal Growth ◽

Bone Growth ◽

Disease Risk ◽

Late Gestation ◽

Protein Diet ◽

Low Protein Diet ◽

Mineral Density ◽

Fetal Bone ◽

Low Protein

Abstract Adverse programming of adult non-communicable disease can be induced by poor maternal nutrition during pregnancy and the periconception period has been identified as a vulnerable period. In the current study, we used a mouse maternal low-protein diet fed either for the duration of pregnancy (LPD) or exclusively during the preimplantation period (Emb-LPD) with control nutrition provided thereafter and postnatally to investigate effects on fetal bone development and quality. This model has been shown previously to induce cardiometabolic and neurological disease phenotypes in offspring. Micro 3D computed tomography examination at fetal stages Embryonic day E14.5 and E17.4, reflecting early and late stages of bone formation, demonstrated LPD treatment caused increased bone formation of relative high mineral density quality in males, but not females, at E14.5, disproportionate to fetal growth, with bone quality maintained at E17.5. In contrast, Emb-LPD caused a late increase in male fetal bone growth, proportionate to fetal growth, at E17.5, affecting central and peripheral skeleton and of reduced mineral density quality relative to controls. These altered dynamics in bone growth coincide with increased placental efficiency indicating compensatory responses to dietary treatments. Overall, our data show fetal bone formation and mineral quality is dependent upon maternal nutritional protein content and is sex-specific. In particular, we find the duration and timing of poor maternal diet to be critical in the outcomes with periconceptional protein restriction leading to male offspring with increased bone growth but of poor mineral density, thereby susceptible to later disease risk.

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Abstract 349: Fetal Growth Restriction Is A Risk Of Vascular Remodeling

Hypertension ◽

10.1161/hyp.64.suppl_1.349 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Toshiyuki Chisaka ◽

Masaki Mogi ◽

Hirotomo Nakaoka ◽

Masataka Kukita ◽

Harumi Kanno ◽

...

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Vascular Injury ◽

Fetal Growth ◽

Femoral Artery ◽

Fetal Growth Restriction ◽

Vascular Remodeling ◽

Growth Restriction ◽

Neointima Formation ◽

Injured Artery

Objects: A number of studies suggest that fetal growth restriction (FGR) promotes a risk of cardiovascular disease and metabolic disorders. However, it has not been well assessed whether FGR would be involved in the exaggeration of vascular remodeling. We investigated the effect of FGR on inflammatory vascular remodeling using cuff- induced vascular injury mouse model. Methods: Dams (C57BL/6J strain mice) were fed with an isocaloric diet containing 20% protein (normal protein; NP) or 8% protein (low protein; LP) from 10 weeks of ages. At the day of delivery, all dams were returned to the NP diet. After weaning, offspring were fed with the NP diet. Vascular injury was induced by polyethylene cuff placement around the femoral artery in offspring at 10 weeks of age. Neointima formation was evaluated by Elastica van Gieson staining 2 weeks after cuff placement. We assessed the following parameters in the femoral arteries prepared one week after cuff placement. Inflammatory cytokine and NADPH oxidase subunit were assessed by RT-PCR. Superoxide anion production, cell proliferation were evaluated by dihydroethidium staining, proliferating cell nuclear antigen (PCNA) staining respectively. p38 mitogen-activated protein kinase (p38MAPK) phosphorylation were evaluated by immunoblot analysis. Results: Birth weight was significantly lower in LP offspring (LPO) compared with NP offspring (NPO); however, LPO showed a similar body weight compared with NPO at 10 weeks of ages. Blood pressure at 12 weeks of age in LPO did not differ from NPO. Neointima formation was more exaggerated in LPO than NPO with enhanced oxidative stress and PCNA index in the injured artery. Expressions of MCP-1, IL-6, IL-1β and TNF-α in the femoral artery were more enhanced in LPO. Moreover, expressions of NADPH oxidase subunits, such as p22phox, p40phox, p47phox, p67phox, gp91phpx, Nox4 and Rac1 in the injured artery were enhanced in LPO than NPO. The phosphorylation level of p38MAPK was more increased in LPO than NPO. Conclusion: FGR led to the enhanced vascular remodeling via enhancement of stress responses such as inflammation and oxidative stress. These results suggest that FGR is a risk of vascular remodeling in the later life after birth.

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Paternal low protein diet affects fetal growth, placental development and skeletal formation in mice

Reproduction Abstracts ◽

10.1530/repabs.3.o023 ◽

2016 ◽

Author(s):

Adam Watkins ◽

Slobodan Sirovica ◽

Ben Stokes ◽

Owen Addison ◽

Richard Martin

Keyword(s):

Fetal Growth ◽

Protein Diet ◽

Low Protein Diet ◽

Placental Development ◽

Low Protein ◽

Skeletal Formation

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Paternal low protein diet and the supplementation of methyl-donors impact fetal growth and placental development in mice

Placenta ◽

10.1016/j.placenta.2020.10.020 ◽

2021 ◽

Vol 103 ◽

pp. 124-133

Author(s):

Hannah L. Morgan ◽

Arwa Aljumah ◽

Charlène Rouillon ◽

Adam J. Watkins

Keyword(s):

Fetal Growth ◽

Protein Diet ◽

Low Protein Diet ◽

Placental Development ◽

Methyl Donors ◽

Low Protein

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Ouabain regulates kidney metabolic profiling in rat offspring of intrauterine growth restriction induced by low-protein diet

Life Sciences ◽

10.1016/j.lfs.2020.118281 ◽

2020 ◽

Vol 259 ◽

pp. 118281

Author(s):

Qien Wang ◽

Jing Yue ◽

Xuan Zhou ◽

Meihong Zheng ◽

Bei Cao ◽

...

Keyword(s):

Metabolic Profiling ◽

Intrauterine Growth Restriction ◽

Growth Restriction ◽

Protein Diet ◽

Low Protein Diet ◽

Intrauterine Growth ◽

Rat Offspring ◽

Low Protein

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Antihypertensive treatment in early postnatal life modulates prenatal dietary influences upon blood pressure in the rat

Clinical Science ◽

10.1042/cs0980269 ◽

2000 ◽

Vol 98 (3) ◽

pp. 269-275 ◽

Cited By ~ 95

Author(s):

Rachel C. SHERMAN ◽

Simon C. LANGLEY-EVANS

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Control Diet ◽

In Utero ◽

Protein Diet ◽

Low Protein Diet ◽

Human Populations ◽

Postnatal Life ◽

Blood Pressure Elevation ◽

Low Protein

Epidemiological evidence from diverse human populations, supported by experimental evidence from animal models, suggests that maternal nutrition during pregnancy is an important fetal programming influence upon cardiovascular disease. Experiments with a low-protein-diet model of rat pregnancy suggest a role for the renin–angiotensin system in the programming mechanism, since fetal undernutrition permanently elevates pulmonary and plasma angiotensin-converting enzyme activity. Long-term beneficial effects of captopril on blood pressure in this model require further investigation in order to clarify the role of angiotensin II. Pregnant rats were fed a control diet containing 18% (w/w) casein as the protein source or a low-protein diet containing 9% (w/w) casein. Between the ages of 2 and 4 weeks postnatally, mothers and their pups were treated with losartan or nifedipine. All pups in the study had blood pressure determined at 4 and 12 weeks of age using a tail cuff. Animals exposed to the low-protein diet in utero and not subjected to drug treatment had elevated blood pressure relative to control rats (mean increase of 27 mmHg; P < 0.001). Treatment of rats exposed to the control diet in utero with either nifedipine or losartan between 2 and 4 weeks of age did not alter their blood pressure. Nifedipine had no effect upon the blood pressure of low-protein-exposed pups, but losartan prevented the blood pressure elevation in these animals. Between 4 and 12 weeks of age, blood pressure increased significantly in all groups (P < 0.001). The pattern of blood pressure among the groups was identical to that observed at 4 weeks, suggesting that the observed early effects of losartan would be maintained into adult life. The data are consistent with the hypothesis that angiotensin II plays a major role in the prenatal programming of hypertension. The action of angiotensin II at the AT1 receptor between 2 and 4 weeks of age may be critically up-regulated by fetal factors, including exposure to glucocorticoids of maternal origin.

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