Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension

Sarasa Isobe, Ramesh V. Nair, Helen Y. Kang, Lingli Wang, Jan-Renier Moonen, Tsutomu Shinohara, Aiqin Cao, Shalina Taylor, Shoichiro Otsuki, David P. Marciano, Rebecca L. Harper, Mir S. Adil, Chongyang Zhang, Mauro Lago-Docampo, Jakob Körbelin, Jesse M. Engreitz, Michael P. Snyder and Marlene Rabinovitch ()
Additional contact information
Sarasa Isobe: Stanford University School of Medicine
Ramesh V. Nair: Stanford University School of Medicine
Helen Y. Kang: Stanford University School of Medicine
Lingli Wang: Stanford University School of Medicine
Jan-Renier Moonen: Stanford University School of Medicine
Tsutomu Shinohara: Stanford University School of Medicine
Aiqin Cao: Stanford University School of Medicine
Shalina Taylor: Stanford University
Shoichiro Otsuki: Stanford University
David P. Marciano: Stanford University School of Medicine
Rebecca L. Harper: Stanford University
Mir S. Adil: Stanford University School of Medicine
Chongyang Zhang: Stanford University School of Medicine
Mauro Lago-Docampo: Stanford University School of Medicine
Jakob Körbelin: University Medical Center Hamburg-Eppendorf
Jesse M. Engreitz: Stanford University School of Medicine
Michael P. Snyder: Stanford University School of Medicine
Marlene Rabinovitch: Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2-/-) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm-/-). Gene expression analysis of EC-Atm-/- and EC-Bmpr2-/- lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2-/- mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.

Date: 2023
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DOI: 10.1038/s41467-023-43039-y

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