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

## TL;DR

This study shows how reduced levels of CPSF5, an RNA-binding protein, contribute to vascular remodeling in pulmonary hypertension, a severe condition in systemic sclerosis patients.

## Contribution

The study identifies CPSF5 and miR-3163 as key regulators of vascular remodeling through alternative polyadenylation in pulmonary hypertension.

## Key findings

- Reduced Nudt21/CPSF5 in PASMCs leads to increased right ventricle systolic pressure and smooth muscle proliferation.
- CPSF5 reduction causes 3′UTR shortening of PTGER3 and CBFB, stabilizing RUNX1 and promoting proliferation.
- miR-3163 is a novel negative regulator of NUDT21 in pulmonary hypertension, validated in patient samples.

## Abstract

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) Nudt21, 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 Nudt21 under normoxic conditions, recapitulating features of hypoxia–sugen exposure. Our studies reveal that reduced CPSF5 leads to 3′ untranslated region shortening of PTGER3 and CBFB, the latter contributing to increased levels of proliferative transcription factor RUNX1. We also identify miR‐3163 as novel negative regulator of NUDT21 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.

Increased miR‐3163 targets NUDT21, reducing CPSF5 levels and driving APA dysregulation. This results in 3′UTR shortening of CBFB, which stabilizes RUNX1 and promotes smooth muscle proliferation. PTGER3, is also shortened amplifying hypoxia‐induced RVSP. Together, these pathways contribute to vascular remodeling in PH.

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