Nitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension (PAH). However, the role of nitrative stress in the pathogenesis of obliterative vascular remolding and severe PAH remains largely unclear. Our recent studies identified a novel mouse model [Egln1Tie2Cre, Egln1 encoding prolyl hydroxylase 2 (PHD2)] with obliterative vascular remodeling and right heart failure, which provides us an excellent model to study the role of nitrative stress in obliterative vascular remodeling. Here we show that nitrative stress was markedly elevated whereas endothelial Caveolin-1 expression was suppressed in the lungs of Egln1Tie2Cre mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP) or endothelial Nos3 knockdown using endothelial cell-targeted nanoparticle delivery of CRISPR-Cas9/gRNA plasmid DNA inhibited obliterative pulmonary vascular remodeling and attenuated severe PH in Egln1Tie2Cre mice. Genetic restoration of Cav1 expression in Egln1Tie2Cre mice normalized nitrative stress, reduced PH and improved right heart function. These data suggest that suppression of Caveolin-1 expression secondary to PHD2 deficiency augments nitrative stress through eNOS activation, which contributes to obliterative vascular remodeling and severe PH. Thus, reactive oxygen/nitrogen species scavenger might have therapeutic potential for the inhibition of obliterative vascular remodeling and severe PAH.
Rationale: Rare genetic variants and genetic variation at loci in an enhancer in SRY-Box Transcription Factor 17 (SOX17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutation in SOX17 in PAH pathogenesis has not been reported. Objectives: To investigate the role of SOX17 deficiency in pulmonary hypertension (PH) development. Methods: Human lung tissue and endothelial cells (ECs) from IPAH patients were used to determine the expression of SOX17. Tie2Cre-mediated and EC-specific deletion of Sox17 mice were assessed for PH development. Single-cell RNA sequencing analysis, human lung ECs, and smooth muscle cell culture were performed to determine the role and mechanisms of SOX17 deficiency. A pharmacological approach was used in Sox17 deficiency mice for therapeutic implication. Measurement and Main Results: SOX17 expression was downregulated in the lungs and pulmonary ECs of IPAH patients. Mice with Tie2Cre mediated Sox17 knockdown and EC-specific Sox17 deletion developed spontaneously mild PH. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced PH in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and anti-apoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP signaling. E2F Transcription Factor 1 (E2F1) signaling was shown to mediate the SOX17 deficiency-induced EC dysfunction and PH development. Conclusions: Our study demonstrated that endothelial SOX17 deficiency induces PH through E2F1 and targeting E2F1 signaling represents a promising approach in PAH patients.
Endothelial cells (ECs) line the inner wall of blood vessels and maintain tissue homeostasis by preserving vascular integrity via blood flow regulation and exchanging oxygen and nutrients. The heterogeneity of ECs across different organs was recently explored using single-cell RNA-sequencing (scRNA-seq) by multiple studies. Compared to other organs, the lung exhibits a distinct morphology composed of a thin layer of capillary ECs for efficient gas exchange. In this study, we demonstrate that Tmem100 is a lung-specific endothelium gene using scRNA-seq and lineage tracing approaches.
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