Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia

Research output: Contribution to journalArticle

Authors

  • Aneel R. Bhagwani
  • Daniela Farkas
  • Brennan Harmon
  • Kayla J. Authelet
  • Carlyne D. Cool
  • Martin Kolb
  • Elena Goncharova
  • Mervin C. Yoder
  • Matthias Clauss
  • Robert Freishtat
  • Laszlo Farkas

External Institution(s)

  • Virginia Commonwealth University
  • Ohio State University
  • Children's National Medical Center
  • University of Colorado Denver
  • McMaster University
  • University of Pittsburgh
  • Indiana University-Purdue University Indianapolis

Details

Original languageEnglish (US)
Article number1136
JournalScientific reports
Volume10
Issue number1
StatusPublished - Dec 1 2020
Peer-reviewedYes

Abstract

One current concept suggests that unchecked proliferation of clonally selected precursors of endothelial cells (ECs) contribute to severe pulmonary arterial hypertension (PAH). We hypothesized that clonally selected ECs expressing the progenitor marker CD117 promote severe occlusive pulmonary hypertension (PH). The remodelled pulmonary arteries of PAH patients harboured CD117+ ECs. Rat lung CD117+ ECs underwent four generations of clonal expansion to enrich hyperproliferative ECs. The resulting clonally enriched ECs behaved like ECs, as measured by in vitro and in vivo angiogenesis assays. The same primitive ECs showed a limited ability for mesenchymal lineage differentiation. Endothelial differentiation and function were enhanced by blocking TGF-β signalling, promoting bone morphogenic protein (BMP) signalling. The transplantation of the EC clones caused arterio-occlusive PH in rats exposed to chronic hypoxia. These EC clones engrafted in the pulmonary arteries. Yet cessation of chronic hypoxia promoted lung cell apoptosis and resolution of vascular lesions. In conclusion, this is to the best of our knowledge, the first report that clonally enriched primitive ECs promote occlusive pulmonary arteriopathy and severe PH. These primitive EC clones further give rise to cells of endothelial and mesenchymal lineage as directed by BMP and TGF-β signaling.

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Bhagwani, AR, Farkas, D, Harmon, B, Authelet, KJ, Cool, CD, Kolb, M, Goncharova, E, Yoder, MC, Clauss, M, Freishtat, R & Farkas, L 2020, 'Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia', Scientific reports, vol. 10, no. 1, 1136. https://doi.org/10.1038/s41598-020-58083-7