MrgD as a Novel Modeling and Treatment Target for Pulmonary Hypertension

The hyperproliferation of smooth muscle cells and deposition of collagen in the pulmonary artery are among the primary characteristics of pulmonary hypertension (PH). These processes contribute to vascular remodeling, ultimately leading to elevated pulmonary artery pressure and right ventricular failure. The MrgD (Mas-related G-protein-coupled receptor member D) exhibits close associations with certain cardiovascular diseases; however, its role in PH remains unclear.

The effects of the absence or activation of MrgD on PH were investigated using PH animal models induced by Sugen5416+hypoxia, monocrotaline, as well as global or smooth muscle-specific knockout of MrgD. Signaling pathways regulated by MrgD were investigated using high-throughput screening of data from single-cell sequencing of mouse lungs and RNA sequencing of human pulmonary artery smooth muscle cells, as well as other molecular biology experiments.

We observed decreased MrgD levels in animal models and patients with PH. Both global and conditional knockout of MrgD exacerbated hypoxia-induced PH in mice. MrgD activation attenuated the PH phenotypes in several established models, although these protective effects were reversed in MrgD-knockout mice. Transcriptome analysis revealed a significantly differentially expressed gene, PIM1 (proviral integration site for Moloney murine leukemia virus 1), as a potential MrgD target. Silencing MrgD increased pulmonary artery smooth muscle cell proliferation by facilitating the AKT (protein kinase B)-mediated interaction of MAZ (MYC-associated Zinc-finger protein) with PIM1. MrgD activation inhibited this pathway and was ineffective in PH mice with pulmonary artery smooth muscle cells overexpressing PIM1.

MrgD deficiency in pulmonary arterioles increases susceptibility to PH, particularly in a hypoxic environment. MrgD is a potential modeling and therapeutic target for PH.