Pregnancy hormones increase cardiac capillary density via the PGC-1α /ERRα /VEGF-pathway in cardiomyocytes

Michael Hesse^1*Daniel Korzus¹Kristina Thaben¹Nicole Wagner²Süleyman Ergün²Zolt Arany³Bernd K. Fleischmann^1*

• ¹University of Bonn, Bonn, Germany
• ²Julius-Maximilians-Universitat Wurzburg, Würzburg, Germany
• ³University of Pennsylvania Perelman School of Medicine, Philadelphia, United States

Pregnancy significantly affects the maternal cardiovascular system, and its physiological adaptation is characterized by cardiac hypertrophy and increased capillarization. The molecular mechanisms underlying these adaptations are not yet fully understood. Therefore, we analyzed them in mouse hearts at different stages of pregnancy and after hormone treatment. We analyzed cell proliferation, capillary density, hypertrophy and gene expression using immunostainings, and differential gene expression by quantitative RT-PCR in mouse hearts at different stages during pregnancy and after treatment with combinations of progesterone and estrogen for up to 14 days. We found that the number of proliferating cells in the hearts of pregnant mice increased starting gestational day 3 (GD3), peaked at GD14, mainly in fibroblasts and endothelial cells (ECs), but not in cardiomyocytes (CMs), and decreased immediately after delivery. The proliferation of ECs was indicative of angiogenesis, as evidenced by an increase in capillary density. After hormone treatment, capillary density increased in the heart in both female and male mice, without prominent CM hypertrophy, and independently of nuclear hormone receptors. The proportion of proliferating cardiac cells and ECs was significantly increased after 14 days of treatment. Mechanistically, we identified activation of the PGC-1α/ERRα signaling pathway and upregulation of its downstream target VEGFA. By using a CM-specific PGC-1α knockout mouse line, we demonstrated that the pregnancy hormone-induced angiogenesis is induced via PGC-1α signaling in CMs by secretion of VEGF. Our data indicated a direct effect of pregnancy hormones on cardiac capillarization, rather than indirect effects through CM hypertrophy, and demonstrate that capillary expansion is not sufficient to drive physiological hypertrophy. Pregnancy hormones directly act on CMs via the PGC-1α/ERRα signaling pathway and VEGF secretion, positioning CMs as a key source of angiogenic factors that promote endothelial cell proliferation and enhance capillary density in the heart.