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Interleukin-6 is critical in the development of gcn2-mutation associated pulmonary veno-occlusive disease in mice

ABSTRACT: Biallelic mutations in eukaryotic translation initiation factor 2 α kinase 4, EIF2AK4 (which encodes general control nonderepressible 2, GCN2) underpin heritable forms of pulmonary veno-occlusive disease (PVOD), a rare and fatal form of pulmonary hypertension. The mechanisms linking these remain uncharacterised. We demonstrate for the first time that homozygous loss of gcn2 is sufficient to cause mild pulmonary hypertension in mice. Single-cell transcriptomics of mouse lungs identified adventitial fibroblasts as having the greatest GCN2-dependent transcriptional differences, implicating them as key players in this model of PVOD. The most significantly upregulated pathways in gcn2-/- adventitial fibroblasts were inflammatory, and therefore we went on to demonstrate a pro-inflammatory phenotype in gcn2-/- mouse embryonic fibroblasts and gcn2-/- mice. When chronically exposed to lipopolysaccharide, the pulmonary hypertensive phenotype of gcn2-/- mice is exaggerated. Genetic ablation of interleukin-6 completely rescues both baseline and LPS-exaggerated pulmonary hypertensive phenotype. In an orthogonal murine model of pulmonary hypertension induced by exposure to mitomycin-C, deletion of interleukin-6 again rescued the pulmonary vascular phenotype. Targeting Il6-dependent pathways may be useful in treating this deadly disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE294702 | GEO | 2026/06/10

REPOSITORIES: GEO

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Project description:Vascular aging is directly related to several major diseases including hypertension and atherosclerosis, in which endothelial dysfunction and smooth muscle phenotype changes are crucial. However, cell types within the vessel wall and their dynamic cellular communication status have not been characterized in different arteries during hypertensive aging. To depict the interconnectedness of complex mechanism between hypertension and aging, we performed single cell RNA sequencing of aorta, femoral and mesentery artery, respectively from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) aging 16-72 weeks. We found that aging and hypertension alone have a significant impact on the alteration of cellular composition and artery remodeling both on conductive and resistant arteries, even greater when superimposed. Consistently, smooth muscle cells (SMCs) underwent phenotypic switching from contractile towards synthetic, apoptotic and senescent SMCs with aging/hypertension. We identified three sub-clusters of Spp1high synthetic SMCs, Spp1high matrix activated fibroblasts and Spp1high scar-associated macrophage involved in hypertensive aging, highlighting that Spp1, encoding protein osteopontin (OPN), could be a potential regulator participating in hypertensive aging. Spp1high scar-associated macrophage enriched for ROS metabolic process, supramolecular fiber organization and actin filament organization. Cell-cell communication analysis also revealed SPP1-Cd44 receptor pairing was markedly aggravated on hypertensive aging condition. Importantly, the concentration of OPN in human serum significantly potentiated in hypertension patient compared with normal group. Thus, we provide a comprehensive cell atlas to systematically resolve the cellular diversity and dynamic cellular communication changes of the vessel wall during hypertensive aging, highlight the mechanisms of vascular vasodilation through cGMP-PKG signaling pathway and identified a protein marker osteopontin as a potential regulator of vascular remodeling during hypertensive aging.

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Interleukin-6 is critical in the development of gcn2-mutation associated pulmonary veno-occlusive disease in mice

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