Sex differences in the proliferation of pulmonary artery endothelial cells: Implications for plexiform arteriopathy

Shanshan Qin, Dan N. Predescu, Monal Patel, Patrick Drazkowski, Balaji Ganesh, Sanda A. Predescu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The sex-biased disease pulmonary arterial hypertension (PAH) is characterized by the proliferation and overgrowth of dysfunctional pulmonary artery endothelial cells (PAECs). During inflammation associated with PAH, granzyme B cleaves intersectin-1 to produce N-terminal (EHITSN) and C-terminal (SH3A-EITSN) protein fragments. In a murine model of PAH, EHITSN triggers plexiform arteriopathy via p38-ELK1-c-Fos signaling. The SH3A-EITSN fragment also influences signaling, having dominant-negative effects on ERK1 and ERK2 (also known as MAPK3 and MAPK1, respectively). Using PAECs engineered to express tagged versions of EHITSN and SH3A-EITSN, we demonstrate that the two ITSN fragments increase both p38-ELK1 activation and the ratio of p38 to ERK1 and ERK2 activity, leading to PAEC proliferation, with female cells being more responsive than male cells. Furthermore, expression of EHITSN substantially upregulates the expression and activity of the long noncoding RNA Xist in female PAECs, which in turn upregulates the X-linked gene ELK1 and represses expression of krüppel-like factor 2 (KLF2). These events are recapitulated by the PAECs of female idiopathic PAH patients, and may account for their proliferative phenotype. Thus, upregulation of Xist could be an important factor in explaining sexual dimorphism in the proliferative response of PAECs and the imbalanced sex ratio of PAH.

Original languageEnglish (US)
Article numberjcs237776
JournalJournal of cell science
Volume133
Issue number9
DOIs
StatePublished - May 2020

Keywords

  • C-Fos
  • ELK1
  • Endothelial cells
  • Intersectin
  • KLF2
  • LncRNA Xist
  • P38 to ERK1/2 activity ratio
  • Plexiform phenotype
  • Proliferation
  • Sexual dimorphism

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Sex differences in the proliferation of pulmonary artery endothelial cells: Implications for plexiform arteriopathy'. Together they form a unique fingerprint.

Cite this