Cellular senescence impairs the reversibility of pulmonary arterial hypertension

Diederik E. van der Feen, Guido P.L. Bossers, Quint A.J. Hagdorn, Jan Renier Moonen, Kondababu Kurakula, Robert Szulcek, James Chappell, Francesco Vallania, Michele Donato, Klaas Kok, Jaskaren S. Kohli, Arjen H. Petersen, Tom van Leusden, Marco Demaria, Marie José T.H. Goumans, Rudolf A. De Boer, Purvesh Khatri, Marlene Rabinovitch, Rolf M.F. Berger, Beatrijs Bartelds

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Pulmonary arterial hypertension (PAH) in congenital cardiac shunts can be reversed by hemodynamic unloading (HU) through shunt closure. However, this reversibility potential is lost beyond a certain point in time. The reason why PAH becomes irreversible is unknown. In this study, we used MCT+shunt-induced PAH in rats to identify a dichotomous reversibility response to HU, similar to the human situation. We compared vascular profiles of reversible and irreversible PAH using RNA sequencing. Cumulatively, we report that loss of reversibility is associated with a switch from a proliferative to a senescent vascular phenotype and confirmed markers of senescence in human PAH-CHD tissue. In vitro, we showed that human pulmonary endothelial cells of patients with PAH are more vulnerable to senescence than controls in response to shear stress and confirmed that the senolytic ABT263 induces apoptosis in senescent, but not in normal, endothelial cells. To support the concept that vascular cell senescence is causal to the irreversible nature of end-stage PAH, we targeted senescence using ABT263 and induced reversal of the hemodynamic and structural changes associated with severe PAH refractory to HU. The factors that drive the transition from a reversible to irreversible pulmonary vascular phenotype could also explain the irreversible nature of other PAH etiologies and provide new leads for pharmacological reversal of end-stage PAH.

Original languageEnglish
Article numbereaaw4974
JournalScience Translational Medicine
Volume12
Issue number554
DOIs
Publication statusPublished - 29 Jul 2020

Cite this

van der Feen, D. E., Bossers, G. P. L., Hagdorn, Q. A. J., Moonen, J. R., Kurakula, K., Szulcek, R., ... Bartelds, B. (2020). Cellular senescence impairs the reversibility of pulmonary arterial hypertension. Science Translational Medicine, 12(554), [eaaw4974]. https://doi.org/10.1126/scitranslmed.aaw4974