Journalartikel

Jahr der Veröffentlichung: 2022

Seiten: 721-728

Zeitschrift: Pediatric Research

Bandnummer: 92

Heftnummer: 3

ISSN: 0031-3998

eISSN: 1530-0447

Open Access Status: Green

DOI Link: https://doi.org/10.1038/s41390-021-01843-6

Verlag: Springer Nature [academic journals on nature.com]

Abstract: 
Background Endothelial-to-mesenchymal-transition (EndMT) plays a major role in cardiac fibrosis, including endocardial fibroelastosis but the stimuli are still unknown. We developed an endothelial cell (EC) culture and a whole heart model to test whether mechanical strain triggers TGF-beta-mediated EndMT. Methods Isolated ECs were exposed to 10% uniaxial static stretch for 8 h (stretch) and TGF-beta-mediated EndMT was determined using the TGF-beta-inhibitor SB431542 (stretch + TGF-beta-inhibitor), BMP-7 (stretch + BMP-7) or losartan (stretch + losartan), and isolated mature and immature rats were exposed to stretch through a weight on the apex of the left ventricle. Immunohistochemical staining for double-staining with endothelial markers (VE-cadherin, PECAM1) and mesenchymal markers (alpha SMA) or transcription factors (SLUG/SNAIL) positive nuclei was indicative of EndMT. Results Stretch-induced EndMT in ECs expressed as double-stained ECs/total ECs (cells: 46 +/- 13%; heart: 15.9 +/- 2%) compared to controls (cells: 7 +/- 2%; heart: 3.1 +/- 0.1; p < 0.05), but only immature hearts showed endocardial EndMT. Inhibition of TGF-beta decreased the number of double-stained cells significantly, comparable to controls (cells/heart: control: 7 +/- 2%/3.1 +/- 0.1%, stretch: 46 +/- 13%/15 +/- 2%, stretch + BMP-7: 7 +/- 2%/2.9 +/- 0.1%, stretch + TGF-beta-inhibitor (heart only): 5.2 +/- 1.3%, stretch + losartan (heart only): 0.89 +/- 0.1%; p < 0.001 versus stretch). Conclusions Endocardial EndMT is an age-dependent consequence of increased strain triggered by TGF- beta activation. Local inhibition through either rebalancing TGF-beta/BMP or with losartan was effective to block EndMT. Impact Mechanical strain imposed on the immature LV induces endocardial fibroelastosis (EFE) formation through TGF-beta-mediated activation of endothelial-to-mesenchymal transition (EndMT) in endocardial endothelial cells but has no effect in mature hearts. Local inhibition through either rebalancing the TGF-beta/BMP pathway or with losartan blocks EndMT. Inhibition of endocardial EndMT with clinically applicable treatments may lead to a better outcome for congenital heart defects associated with EFE.

Harvard-Zitierstil: Vorisek, C., Weixler, V., Dominguez, M., Axt-Fliedner, R., Hammer, P., Lin, R., et al. (2022) Mechanical strain triggers endothelial-to-mesenchymal transition of the endocardium in the immature heart, Pediatric Research, 92(3), pp. 721-728. https://doi.org/10.1038/s41390-021-01843-6

APA-Zitierstil: Vorisek, C., Weixler, V., Dominguez, M., Axt-Fliedner, R., Hammer, P., Lin, R., Melero-Martin, J., del Nido, P., & Friehs, I. (2022). Mechanical strain triggers endothelial-to-mesenchymal transition of the endocardium in the immature heart. Pediatric Research. 92(3), 721-728. https://doi.org/10.1038/s41390-021-01843-6