bioRxiv : the preprint server for biology · 2025
Decreased endothelial cell retinoic acid signaling accelerates progression of single ventricle pulmonary arteriovenous malformations.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Rousseau Henry, Wan Tina, Nguyen Nhi, Andrae Jaime Wendt, Tschannen Michael, Mathison Angela J, Jin Victor, Groh Olivia, Zhou Xingyan, Meadows Stryder M, Ramchandran Ramani, Shmarakov Igor, Pan Amy Y, Spearman Andrew D
Аннотация
BACKGROUND: Pulmonary arteriovenous malformations (PAVMs) are vascular complications that universally develop in patients with single ventricle congenital heart disease after Glenn surgery. However, the pathophysiological mechanisms underlying single ventricle PAVMs are poorly understood. To comprehensively evaluate molecular changes post-Glenn, we performed single-cell RNA sequencing (scRNAseq) on rat lung samples after Glenn surgery.
METHODS: Using adult Sprague Dawley rats, we performed scRNAseq on unfiltered lung samples 3 weeks after left-sided Glenn or sham surgery. We compared endothelial cell (EC) differentially expressed genes (DEGs) in our model to two mouse models of hereditary hemorrhagic telangiectasia (HHT), a hereditary condition characterized by visceral AVMs. Finally, we modified the vitamin A (Vit A) content of Glenn and sham rat diets and re-assessed PAVM shunting and EC transcriptional differences.
RESULTS: Using scRNAseq (n=4 Glenn, n=4 sham), we identified 13 transcriptionally distinct lung cell clusters, including 3 EC clusters (general, capillary, lymphatic), with pronounced differences between Glenn and sham in the general EC cluster (~17% of genes). Comparison to HHT mouse models confirmed overlap of ~18% of DEGs, including identification of significantly downregulated genes involved in and regulated by all-trans retinoic acid (ATRA) signaling in all 3 models. Dietary deficiency of Vit A intake, a precursor of ATRA, caused increased PAVM shunting (p<0.01) that was mitigated with excess dietary Vit A intake. Lastly, EC-specific RNAseq identified Vit A diet-induced gene expression differences, including regulation of PI3K signaling.
CONCLUSIONS: In this study, we report the novel application of scRNAseq to study mechanisms underlying single ventricle PAVMs in a surgical rat model. We identified multiple dysregulated biological processes in rat lung ECs post-Glenn, including decreased ATRA signaling and conserved gene expression patterns with HHT. Dietary modification of Vit A intake altered post-Glenn shunting and represents a novel potential therapeutic strategy for single ventricle PAVMs and HHT AVMs.
METHODS: Using adult Sprague Dawley rats, we performed scRNAseq on unfiltered lung samples 3 weeks after left-sided Glenn or sham surgery. We compared endothelial cell (EC) differentially expressed genes (DEGs) in our model to two mouse models of hereditary hemorrhagic telangiectasia (HHT), a hereditary condition characterized by visceral AVMs. Finally, we modified the vitamin A (Vit A) content of Glenn and sham rat diets and re-assessed PAVM shunting and EC transcriptional differences.
RESULTS: Using scRNAseq (n=4 Glenn, n=4 sham), we identified 13 transcriptionally distinct lung cell clusters, including 3 EC clusters (general, capillary, lymphatic), with pronounced differences between Glenn and sham in the general EC cluster (~17% of genes). Comparison to HHT mouse models confirmed overlap of ~18% of DEGs, including identification of significantly downregulated genes involved in and regulated by all-trans retinoic acid (ATRA) signaling in all 3 models. Dietary deficiency of Vit A intake, a precursor of ATRA, caused increased PAVM shunting (p<0.01) that was mitigated with excess dietary Vit A intake. Lastly, EC-specific RNAseq identified Vit A diet-induced gene expression differences, including regulation of PI3K signaling.
CONCLUSIONS: In this study, we report the novel application of scRNAseq to study mechanisms underlying single ventricle PAVMs in a surgical rat model. We identified multiple dysregulated biological processes in rat lung ECs post-Glenn, including decreased ATRA signaling and conserved gene expression patterns with HHT. Dietary modification of Vit A intake altered post-Glenn shunting and represents a novel potential therapeutic strategy for single ventricle PAVMs and HHT AVMs.