Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction

Menendez-Castro, Carlos; Toka, Okan; Fahlbusch, Fabian; Cordasic, Nada; Wachtveitl, Rainer; Hilgers, Karl F.; Rascher, Wolfgang; Hartner, Andrea

doi:10.1038/pr.2014.27

Cited by 27 publications

(35 citation statements)

References 40 publications

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“…Despite slightly reduced LV mass and wall thickness and a reduced number of cardiomyocytes, adult hearts after prenatal rapamycin treatment exhibit normal contractility and complete recovery of cardiac output as compared with neonatal stages without signs of maladaptive myocardial remodeling. This is consistent with some rodent studies showing unaltered LV contractility after IUGR under baseline conditions in adulthood, but others have reported reduced heart function at 10 to 12 weeks of age . Similarly, most IUGR animal models eventually show increased myocardial fibrosis with age, whereas the onset of tissue remodeling in early adulthood is less clear .…”

Section: Discussionsupporting

confidence: 90%

Prenatal Mechanistic Target of Rapamycin Complex 1 (m TORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterine Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function

Hennig

Fiedler

Jux

et al. 2017

JAHA

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BackgroundFetal growth impacts cardiovascular health throughout postnatal life in humans. Various animal models of intrauterine growth restriction exhibit reduced heart size at birth, which negatively influences cardiac function in adulthood. The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and growth factor availability with cell growth, thereby regulating organ size. This study aimed at elucidating a possible involvement of mTORC1 in intrauterine growth restriction and prenatal heart growth.Methods and ResultsWe inhibited mTORC1 in fetal mice by rapamycin treatment of pregnant dams in late gestation. Prenatal rapamycin treatment reduces mTORC1 activity in various organs at birth, which is fully restored by postnatal day 3. Rapamycin‐treated neonates exhibit a 16% reduction in body weight compared with vehicle‐treated controls. Heart weight decreases by 35%, resulting in a significantly reduced heart weight/body weight ratio, smaller left ventricular dimensions, and reduced cardiac output in rapamycin‐ versus vehicle‐treated mice at birth. Although proliferation rates in neonatal rapamycin‐treated hearts are unaffected, cardiomyocyte size is reduced, and apoptosis increased compared with vehicle‐treated neonates. Rapamycin‐treated mice exhibit postnatal catch‐up growth, but body weight and left ventricular mass remain reduced in adulthood. Prenatal mTORC1 inhibition causes a reduction in cardiomyocyte number in adult hearts compared with controls, which is partially compensated for by an increased cardiomyocyte volume, resulting in normal cardiac function without maladaptive left ventricular remodeling.ConclusionsPrenatal rapamycin treatment of pregnant dams represents a new mouse model of intrauterine growth restriction and identifies an important role of mTORC1 in perinatal cardiac growth.

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Section: Discussionsupporting

confidence: 90%

Prenatal Mechanistic Target of Rapamycin Complex 1 (m TORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterine Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function

Hennig

Fiedler

Jux

et al. 2017

JAHA

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“…In the rat study by Mendendez‐Castro et al . (), however, low protein IUGR decreased EF, increased end‐systolic and end‐diastolic diameters, and decreased wall thickness discernible at 70 days of age. In studies by Zohdi et al .…”

Section: Discussionmentioning

confidence: 82%

“…, ; Menendez‐Castro et al . ). Remarkably, whereas increased end‐systolic sphericity index and associated elevated normalized end‐systolic volume were observed with IUGR, no similar appreciable change was noted in the OLD animals.…”

Section: Discussionmentioning

confidence: 97%

Cardiac remodelling in a baboon model of intrauterine growth restriction mimics accelerated ageing

Kuo

et al. 2016

The Journal of Physiology

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Extensive rodent studies have shown that reduced perinatal nutrition programmes chronic cardiovascular disease. To enable translation to humans, we developed baboon offspring cohorts from mothers fed ad libitum (control) or 70% of the control ad libitum diet in pregnancy and lactation, which were growth restricted at birth. We hypothesized that intrauterine growth restriction (IUGR) offspring hearts would show impaired function and a premature ageing phenotype. We studied IUGR baboons (8 male, 8 female, 5.7 years), control offspring (8 male, 8 female, 5.6 years - human equivalent approximately 25 years), and normal elderly (OLD) baboons (6 male, 6 female, mean 15.9 years). Left ventricular (LV) morphology and systolic and diastolic function were evaluated with cardiac MRI and normalized to body surface area. Two-way ANOVA by group and sex (with P < 0.05) indicated ejection fraction, 3D sphericity indices, cardiac index, normalized systolic volume, normalized LV wall thickness, and average filling rate differed by group. Group and sex differences were found for normalized LV wall thickening and normalized myocardial mass, without interactions. Normalized peak LV filling rate and diastolic sphericity index were not correlated in control but strongly correlated in OLD and IUGR baboons. IUGR programming in baboons produces myocardial remodelling, reduces systolic and diastolic function, and results in the emergence of a premature ageing phenotype in the heart. To our knowledge, this is the first demonstration of the specific characteristics of cardiac programming and early life functional decline with ageing in an IUGR non-human primate model. Further studies across the life span will determine progression of cardiac dysfunction.

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“…Frozen renal tissue was homogenized, protein samples were prepared as described (Menendez-Castro et al, 2014) and separated on a denaturing SDS-PAGE gel (Laemmli, 1970). After electrophoresis, the gels were electroblotted onto PVDF membranes (Hybond-P, GE Amersham, Munich, Germany), blocked with Rotiblock (Roth, Karlsruhe, Germany) for 1 h and incubated overnight with a primary antibody to VEGF-A (ab46154, Abcam, 1:1000).…”

Section: Methodsmentioning

confidence: 99%

“…Reactions without Multiscribe reverse transcriptase were used as negative controls for genomic DNA contamination. PCR was performed with an ABI PRISM 7000 Sequence Detector System and TaqMan or SYBR Green Universal PCR Master Mix (Applied Biosystems), as described previously (Menendez-Castro et al, 2014). All samples were run in triplicates.…”

Section: Methodsmentioning

confidence: 99%

Impaired Neovascularization and Reduced Capillary Supply in the Malignant vs. Non-malignant Course of Experimental Renovascular Hypertension

et al. 2016

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Malignant hypertension develops in some cases of hypertension but not in others. We hypothesized that an impaired neovascularization and a reduced capillary supply characterizes the malignant course of experimental hypertension. Two-kidney, one-clip renovascular hypertension was induced in rats; controls (sham) were sham operated. To distinguish malignant hypertension from non-malignant hypertension, we considered two factors: weight loss, and the number of typical vascular lesions (onion skin lesions and fibrinoid necroses) per kidney section of the nonclipped kidney. Animals in the upper half for both criteria were defined as malignant hypertensives. After 5 weeks, mean arterial blood pressure was elevated to the same degree in malignant hypertension and non-malignant hypertension whereas plasma renin and aldosterone were significantly higher in malignant hypertensives. The expression of plasminogen activator inhibitor-1 was elevated (up to 14-fold) in non-malignant but significantly more increased (up to 36-fold) in malignant hypertensive rats, compared to sham. As a bioassay for neovascularization, the area of granulation tissue ingrowth in polyvinyl discs (implanted subcutaneously) was reduced in malignant hypertension compared to non-malignant hypertension and sham, while there was no difference between non-malignant hypertension and sham. The number of renal and left ventricular capillaries was significantly lower in malignant hypertension compared to non-malignant hypertension, as was the number of proliferating endothelial cells. We conclude that an impaired neovascularization and capillarization occurs in malignant renovascular hypertension but not in the non-malignant course of the disease despite comparable blood pressure levels. This might contribute to the unique vascular lesions and progressive target organ damage observed in malignant hypertension.

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Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction

Cited by 27 publications

References 40 publications

Prenatal Mechanistic Target of Rapamycin Complex 1 (m TORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterine Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function

Prenatal Mechanistic Target of Rapamycin Complex 1 (m TORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterine Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function

Cardiac remodelling in a baboon model of intrauterine growth restriction mimics accelerated ageing

Impaired Neovascularization and Reduced Capillary Supply in the Malignant vs. Non-malignant Course of Experimental Renovascular Hypertension

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