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

Abstract

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.