Onset and Regression of Pregnancy-Induced Cardiac Alterations in Gestationally Hypertensive Mice: The Role of the Natriuretic Peptide System1

Ventura, Nicole M.; Li, Terry Y; Tse, M. Yat; Andrew, R. David; Tayade, Chandrakant; Jin, Albert; Pang, Stephen C.

doi:10.1095/biolreprod.115.132696

Cited by 12 publications

(11 citation statements)

References 51 publications

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“…Previous studies report wet heart weight by itself is increased at late pregnancy or in the postpartum period, and body weight is consistently highest at late pregnancy between 17.5 and 20 days. 5,6,15 Our findings also followed this pattern, although the heart weight was not significantly different in late pregnancy versus non-pregnant animals and was significantly higher in the postpartum period compared to virgin and ed12 pregnant mice. Our studies differ from Umar et al 6 who reported that HW alone was higher in late pregnancy (day 19/20) compared to virgins and had returned to virgin levels at ppd7.…”

Section: Discussionsupporting

confidence: 77%

“…3,4 This type of eccentric hypertrophy is physiological, meaning it is reversible and typically returns to baseline in humans within a few months to a year of parturition. 5 In mice, studies report that cardiac parameters return to baseline within a few days or even up to a month after delivery. [5][6][7] Postpartum or peripartum cardiomyopathy is a pathological condition that occurs in late pregnancy, during delivery or within five months of delivery where the heart fails to remodel to the non-pregnant phenotype and remains dilated; this pathological condition can progress to heart failure.…”

Section: Impact Statementmentioning

confidence: 99%

“…5 In mice, studies report that cardiac parameters return to baseline within a few days or even up to a month after delivery. [5][6][7] Postpartum or peripartum cardiomyopathy is a pathological condition that occurs in late pregnancy, during delivery or within five months of delivery where the heart fails to remodel to the non-pregnant phenotype and remains dilated; this pathological condition can progress to heart failure. As postpartum cardiomyopathy is associated with the physiological changes of pregnancy, understanding the normal heart alterations that occur during pregnancy and its postpartum remodeling period will provide specific targets for further evaluation of the pathological condition.…”

Section: Impact Statementmentioning

confidence: 99%

“…LVIDs were higher in ed18/19 and ppd1. 5 Figure 3. Timp1 mRNA levels were more abundant in late pregnancy ed18/19 and early postpartum ppd1.5 mice than in virgin mice, and Timp1 mRNA in ed18/19 mice was also higher than ed12 mice at midpregnancy.…”

Section: Echocardiographic Assessmentmentioning

confidence: 99%

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Maternal cardiac messenger RNA expression of extracellular matrix proteins in mice during pregnancy and the postpartum period

Parrott

Aljrbi

Biederman

et al. 2018

Exp Biol Med (Maywood)

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Pregnancy creates a condition of cardiac volume overload which leads to physiological eccentric hypertrophy of the heart that is reversed in the postpartum period. Pathological cardiac changes in non-pregnant animals are associated with extracellular matrix remodeling. Based on preliminary microarray findings in the hearts of non-pregnant, pregnant, and postpartum mice, we hypothesized that changes in the expression of extracellular matrix protein genes would accompany functional changes in the heart that occur with reproductive status. Adult left ventricle parameters were evaluated by echocardiography in C57BL/6 mice at diestrous (virgin), and at pregnancy days (eds) 10, 12, and 18/19, and at postpartum days (ppds) 1.5 and 7. Twenty-one left ventricle mRNAs were evaluated including genes for tissue inhibitor of metalloproteinases (Timps), several matrix metallopeptidases (Mmps), collagens (Cols), proteoglycans, and enzymes involved in matrix remodeling at similar days except ed10. Compared to virgin mice, left ventricle internal diameter during diastole and end diastolic volumes significantly increased at ed12, ed18/19, ppd1.5, and ppd7. Left ventricle internal diameter during systole was increased at ed18/19 and ppd1.5, and end systolic volume was increased at ed18/19 compared to virgin mice. Timp1 mRNA levels were higher in late pregnancy and the early postpartum period, and Timp2-4 mRNAs levels were lower at one or both postpartum days compared to specific earlier time points. Mmp3 mRNA levels were higher during late pregnancy and postpartum than earlier in pregnancy. Mmp13 mRNA level was lower at ppd1.5 than late pregnancy, and Mmp15 mRNA level was lowest at ppd7 compared to all other time points. Col1a1 and Col3a1 increased with pregnancy and stayed elevated through ppd7. Col8a1 mRNA was increased on both postpartum days compared to late pregnancy. Our results indicate that late pregnancy and the first week of the postpartum period are an active time for altered expression of extracellular matrix protein genes. Impact statement This study provides the first comprehensive analysis of extracellular matrix protein (ECM) gene expression combined with echocardiographic analyses of heart functional parameters in the murine heart during pregnancy and the early postpartum period. Our findings show regulation of all Timp, selected Mmps, and Col1a1, Col3a1, and Col8a1 mRNA levels with reproductive status, with the greatest number of significant changes occurring in the early postpartum period. Left ventricle cardiac diastolic parameters were the first to change during pregnancy and remained elevated postpartum, whereas systolic parameters were increased in late pregnancy and began to recover during the first week postpartum. These novel findings indicate that although some ECM genes are elevated during late pregnancy, that the postpartum period is a time of robust altered ECM gene expression. These studies provide a basis for examining ECM proteins and their activities in the normal pregnant and postpartum heart and in models of postpartum cardiomyopathy.

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Section: Discussionsupporting

confidence: 77%

Section: Impact Statementmentioning

confidence: 99%

Section: Impact Statementmentioning

confidence: 99%

Section: Echocardiographic Assessmentmentioning

confidence: 99%

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Maternal cardiac messenger RNA expression of extracellular matrix proteins in mice during pregnancy and the postpartum period

Parrott

Aljrbi

Biederman

et al. 2018

Exp Biol Med (Maywood)

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“…Previously, Ventura et al reported that pregnant ANP KO mice had peak cardiac hypertrophy 14 days postpartum with minimal increase in heart weight during pregnancy. 50 However, the ANP KO mice in that study had cardiac hypertrophy prior to pregnancy, which may have blunted the hypertrophic response that was identified in our study where HW/TL and CD were similar between WT and Corin KO mice at 3 and 6 months of age before pregnancy. The cardiac hypertrophy in pregnant Corin KO mice exacerbated when the mice were mated at 6 instead of 3 months of age, indicating that this hypertrophic response to pregnancy worsens with age.…”

Section: Discussionmentioning

confidence: 50%

Pregnancy-Associated Cardiac Hypertrophy in Corin-Deficient Mice: Observations in a Transgenic Model of Preeclampsia

Baird

Wang

et al. 2019

Canadian Journal of Cardiology

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Background: Preeclampsia increases the risk of heart disease. Defects in the protease corin, including the variant T555I/Q568P found in ~12% of blacks, have been associated with preeclampsia and cardiac hypertrophy. The objective of this study is to investigate the role of corin and the T555I/Q568P variant in preeclampsia-associated cardiac alterations using genetically modified mouse models. Methods: Virgin wild-type (WT) and corin knockout mice with or without a cardiac WT corin or T555I/Q568P variant transgene were mated at 3 or 6 months of age. Age- and genotype-matched virgin mice were used as controls. Cardiac morphology and function were assessed at gestational day 18.5 or 28 days postpartum by histological and echocardiographic analyses. Results: Pregnant corin knockout mice at gestational day 18.5 developed cardiac hypertrophy. Such a pregnancy-associated phenotype was not found in WT or corin knockout mice with a cardiac WT corin transgene. Pregnant corin knockout mice with a cardiac T555I/Q568P variant transgene developed cardiac hypertrophy similar to that in pregnant corin knockout mice. The cardiac hypertrophy persisted postpartum in corin knockout mice and was worse if the mice were mated at 6 instead of 3 months of age. There was no hypertrophy-associated decrease in cardiac function in pregnant corin knockout mice. Conclusions: In mice, corin deficiency causes cardiac hypertrophy during pregnancy. Replacement of cardiac WT corin, but not the T555I/Q568P variant found in blacks, rescues this phenotype, indicating a local anti-hypertrophic function of corin in the heart. Corin deficiency may represent an underlying mechanism in preeclampsia-associated cardiomyopathies.

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Developmental origins of pregnancy-induced cardiac changes: establishment of a novel model using the atrial natriuretic peptide gene-disrupted mice

Ventura

Tse

et al. 2018

Mol Cell Biochem

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Pregnancy evokes many challenges on the maternal cardiovascular system that may unmask predispositions for future disease. This is particularly evident for women who develop pregnancy-related disorders, for example, pre-eclampsia and gestational diabetes or hypertension. Such pregnancy-related syndromes increase the risk for cardiovascular disease (CVD) postpartum. As a result, pregnancy has been termed as a cardiovascular stress test and an indicator or marker to predict the development of CVD later in life. In addition, pregnancy-related disorders impact the development of offspring also placing them at a higher risk for disease. Utilizing pregnancy as a physiological stressor, the current investigation sought to determine whether the cardiovascular system of offspring exposed to gestational hypertension in utero would respond adversely to the stress of pregnancy. Heterozygous atrial natriuretic peptide gene-disrupted (ANP) offspring were generated by either crossing male wildtype ANP with female knockout ANP to produce ANP mice or crossing female wildtype ANP with male knockout ANP to produce ANP mice. To study the cardiovascular stress induced by pregnancy, female ANP and ANP mice were mated with male wildtype ANP mice to initiate pregnancy. Cardiac size and molecular expression of the renin-angiotensin (RAS) and natriuretic peptide systems (NPS) were compared between offspring groups. Our data demonstrate that gestational hypertension and lack of maternal ANP did not significantly impact the progression and regression of pregnancy-induced cardiac hypertrophy over gestation and postpartum in ANP offspring. Additionally, the molecular cardiac expression of the RAS and NPS did not differ between offspring groups. Future investigation should assess potential differences in cardiac function and the impact of fetal-programming on offspring cardiovascular adaptations during pregnancy in more severe models of pregnancy-related hypertensive syndrome such as angiotensin II or isoproterenol infusion.

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Onset and Regression of Pregnancy-Induced Cardiac Alterations in Gestationally Hypertensive Mice: The Role of the Natriuretic Peptide System1

Cited by 12 publications

References 51 publications

Maternal cardiac messenger RNA expression of extracellular matrix proteins in mice during pregnancy and the postpartum period

Maternal cardiac messenger RNA expression of extracellular matrix proteins in mice during pregnancy and the postpartum period

Pregnancy-Associated Cardiac Hypertrophy in Corin-Deficient Mice: Observations in a Transgenic Model of Preeclampsia

Developmental origins of pregnancy-induced cardiac changes: establishment of a novel model using the atrial natriuretic peptide gene-disrupted mice

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