During pregnancy the maternal organism undergoes a variety of physiological changes affecting the cardiovascular system. The molecular mechanisms underlying these adaptations are poorly understood.

We have analyzed cell proliferation using immunostainings against pHH3/Ki67 in mouse hearts at different stages during pregnancy. The average percentage of Ki67+ nuclei per total nuclei in cardiac sections increased from virgin controls to gestational day 3 (GD3) and peaked at GD14. The enhanced rate of proliferation stopped immediately after delivery. Co-staining revealed that approximately 2/3 of the proliferating cells were fibroblasts and 1/3 endothelial cells (ECs). The lack of cardiomyocyte (CM) proliferation was corroborated using BrdU pulse chase experiments and analysis of these heartsusing Langendorff perfusion; the results were confirmed by flow cytometric analysis. The proliferation of fibroblasts and ECs appears to reflect angiogenesis and extracellular matrix remodeling known to occur during pregnancy induced hypertrophy. In accordance with these findings we detected CM hypertrophy and increased capillary density during pregnancy. To analyze the role of hormones in these physiological adaptive processes, plasma levels of progesterone, prolactin and estrogen were quantified. Progesterone- and prolactin levels showed their maximal blood plasma concentrations at GD14 and declined at the day of delivery coinciding with the course of proliferation, whereas estrogen displayed two distinct peaks at GD3 and GD18. To mimic the action of pregnancy hormones we implanted hormone-pellets with consistent release for 21 days in ovariectomized mice subcutaneously. Capillary density was significantly increased in mice receiving progesterone-pellets alone or in combination with estrogen-pellets without induction of hypertrophy. Thus, increase of capillary density appears to be caused by progesterone.

We are currently investigating the mechanisms underlying pregnancy hormones induced proliferation in cardiac ECs and fibroblasts.