Pulmonary arterial hypertension (PAH) is a sex-biased disease with a poorly understood female prevalence. Emerging research suggests that nonhormonal factors, such as the XX or XY sex chromosome complement and sex bias in gene expression, may also lead to sex-based differences in PAH incidence, penetrance, and progression. Typically, one of females' two X chromosomes is epigenetically silenced to offer a gender-balanced gene expression. Recent data demonstrate that the long noncoding RNA X-inactive specific transcript, essential for X chromosome inactivation and dosage compensation of X-linked gene expression, shows elevated levels in female PAH lung specimens compared with controls. This molecular event leads to incomplete inactivation of the females' second X chromosome, abnormal expression of X-linked gene(s) involved in PAH pathophysiology, and a pulmonary artery endothelial cell (PAEC) proliferative phenotype. Moreover, the pathogenic proliferative p38 mitogen-activated protein kinase/ETS transcription factor ELK1 (Elk1)/cFos signaling is mechanistically linked to the sexually dimorphic proliferative response of PAECs in PAH. Apprehending the complicated relationship between long noncoding RNA X-inactive specific transcript and X-linked genes and how this relationship integrates into a sexually dimorphic proliferation of PAECs and PAH sex paradox remain challenging. We highlight herein new findings related to how the sex chromosome complement and sex-differentiated epigenetic mechanisms to control gene expression are decisive players in the sexual dimorphism of PAH. Pharmacologic interventions in the light of the newly elucidated mechanisms are discussed.
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