Thursday, December 26, 2024
12/26/2024
ABSTRACT Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by elevated lung pressure, right heart failure, and premature death. Current therapies fail to prevent disease progression due to their inability to suppress and reverse obliterative lesions resulting from vascular remodeling. Previous studies have centered on large arteriolar remodeling in vessels with a diameter >100 µm. However, the role of the capillary bed (vessels <10 µm) in remodeling remains largely ignored. Pericytes (PCs) are indispensable mural cells for maintaining capillary integrity and homeostasis. Our preliminary data showed that the loss of PCs induced excessive capillary and arteriolar remodeling and manifested hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in transgenic animals. Additionally, human idiopathic PAH (IPAH) PCs showed high proliferation and motility, and human IPAH induced-pluripotent stem cells (IPAH-iPSC) derived mural cells lost PCs but gained more smooth muscle characteristics. Vascular organoids derived from IPAH iPSCs further demonstrated a reduced number of endothelial cell (EC) tubes and increased smooth muscle coverage, which recapitulated abnormal vasculature development without PCs. Single-cell RNAseq revealed upregulated expression of the Regulator of G-protein signaling 5 (RGS5) in the IPAH PC cluster, which was validated in IPAH PCs isolated from explanted lungs, hypoxic mouse PCs, and explanted IPAH lung tissues. Thus, we hypothesize that RGS5 overexpression mediates PC dysfunction (detachment and migration) and, in turn, capillary remodeling in IPAH. We proposed to 1) Characterize the impact of PC dysfunction on EC dysfunction, vascular integrity, and remodeling in PC-depleted transgenic animals; 2) determine how RGS5 signaling regulates PC detachment, proliferation/migration, and EC interaction in clinical IPAH samples; 3) Characterize the impact of RGS5 depletion on PC/EC cell-cell interactions in IPAH iPSC vascular organoids. This project will provide novel insight into PC pathobiology in capillary remodeling and establish RGS5 as a potential therapeutic target in PAH, for which the first drugs to treat this devastating disease may be found.
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