Cleavage and Polyadenylation Specificity Factor Subunit 5 Regulates Pulmonary Artery Smooth Muscle Expansion and Hypoxic Response

Pulmonary hypertension (PH) is a fatal condition that affects individuals with systemic sclerosis (SSc), a multiorgan fibrotic disease with limited treatment options. A central feature of PH is vascular remodeling, defined by the narrowing of the arteriole lumen due to cell proliferation and extracellular matrix deposition. Herein, we identify a central mechanism that can regulate multiple transcripts important for vascular remodeling. The highlight of our study is the demonstration that reduced pulmonary artery smooth muscle (PASMC) <i>Nudt21</i>, which codes for the RNA binding protein Cleavage and Polyadenylation Specificity Factor Subunit 5 (CPSF5) The, known to regulate alternative polyadenylation, results in heightened right ventricle systolic pressures in mice exposed to hypoxia-sugen. We also report that increased PASMC proliferation is present in mice with reduced PASMC <i>Nudt21</i> under normoxic conditions, recapitulating features of hypoxia-sugen exposure. Our studies reveal that reduced CPSF5 leads to 3' untranslated region shortening of <i>PTGER3</i> and <i>CBFB</i>, the latter contributing to increased levels of proliferative transcription factor RUNX1. We also identify miR-3163 as novel negative regulator of <i>NUDT21</i> expression in PH. These observations are validated in remodeled vessels from patients with SSc associated with PH and in and point to common mechanisms of RNA processing deficits that contribute to vascular remodeling in PH.