CrossTalk proposal: The mouse SuHx model is a good model of pulmonary arterial hypertension

Penumatsa, Krishna; Warburton, Rod R.; Hill, Nicholas S.

doi:10.1113/jp275864

Cited by 8 publications

(8 citation statements)

References 30 publications

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“…Here, we utilised an endothelial lineage-tracing mouse to assess pulmonary EC responses to PAH with scRNA-seq. With a well-established mouse model of pulmonary hypertension which induces right ventricular hypertrophy and increased RVSP 5,6 , we elucidate the dynamic EC responses at a subpopulation level and across the arteriovenous axis. In addition, our dataset is available for interrogation at http://bakergroup.shinyapps.io/mouse_ec_pah.…”

Section: Cvr-2020-1310mentioning

confidence: 99%

“…Animal models have been developed to study the pathogenesis of PAH. The widely used SuHx mouse model, which utilises Sugen 5416 (SU5416) injection and chronic hypoxia (10% O2), leads to increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy 5,6 . Endothelial cells (ECs) are involved in the primary vascular changes leading to PAH 7 .…”

Section: Introductionmentioning

confidence: 99%

“…The widely used SuHx mouse model, which utilizes Sugen 5416 (SU5416) injection and chronic hypoxia (10% O 2 ), leads to increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy. 5 , 6 …”

Section: Introductionmentioning

confidence: 99%

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Single-cell RNA sequencing profiling of mouse endothelial cells in response to pulmonary arterial hypertension

Rodor

Chen

Scanlon

et al. 2021

Cardiovascular Research

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Aims Endothelial cell dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension (PAH). We aimed to characterise endothelial cell (EC) dynamics in PAH at single-cell resolution. Methods and Results We carried out single-cell RNA sequencing (scRNA-seq) of lung ECs isolated from an EC lineage-tracing mouse model in Control and SU5416/Hypoxia-induced PAH conditions. EC populations corresponding to distinct lung vessel types, including two discrete capillary populations, were identified in both Control and PAH mice. Differential gene expression analysis revealed global PAH-induced EC changes that were confirmed by bulk RNA-seq. This included upregulation of the major histocompatibility complex class II pathway, supporting a role for ECs in the inflammatory response in PAH. We also identified a PAH response specific to the second capillary EC population including upregulation of genes involved in cell death, cell motility and angiogenesis. Interestingly, four genes with genetic variants associated with PAH were dysregulated in mouse ECs in PAH. To compare relevance across PAH models and species, we performed a detailed analysis of EC heterogeneity and response to PAH in rats and humans through whole-lung PAH scRNA-seq datasets, revealing that 51% of up-regulated mouse genes were also up-regulated in rat or human PAH. We identified promising new candidates to target endothelial dysfunction including CD74, the knockdown of which regulates EC proliferation and barrier integrity in vitro. Finally, with an in silico cell ordering approach, we identified zonation-dependent changes across the arteriovenous axis in mouse PAH and showed upregulation of the Serine/threonine-protein kinase Sgk1 at the junction between the macro- and micro-vasculature. Conclusions This study uncovers PAH-induced EC transcriptomic changes at a high resolution, revealing novel targets for potential therapeutic candidate development.

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Section: Cvr-2020-1310mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Single-cell RNA sequencing profiling of mouse endothelial cells in response to pulmonary arterial hypertension

Rodor

Chen

Scanlon

et al. 2021

Cardiovascular Research

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“…Dr Penumatsa and colleagues value the Sugen 5416 injection and chronic hypoxia exposure (SuHx) mouse model for its contribution to the understanding of pulmonary arterial hypertension (PAH) signalling pathways and mechanisms (Penumatsa et al . ). They note that other imperfect animal models have provided insight about pathogenesis and contributed to the development of many therapeutic agents for PAH.…”

mentioning

confidence: 97%

Rebuttal from Sally H. Vitali

Vitali

2018

The Journal of Physiology

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“…As an example, this issue features a Cross‐Talk debate (Vitali, and Penumatsa et al . ) regarding the suitability of the murine model of pulmonary arterial hypertension using the combined insults of vascular endothelial growth factor receptor inhibition and hypoxic exposure as a model for human disease. A review of the literature conducted by Hu et al .…”

mentioning

confidence: 99%

Overview: pulmonary vascular function in health and disease

Shimoda

2019

The Journal of Physiology

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CrossTalk proposal: The mouse SuHx model is a good model of pulmonary arterial hypertension

Cited by 8 publications

References 30 publications

Single-cell RNA sequencing profiling of mouse endothelial cells in response to pulmonary arterial hypertension

Single-cell RNA sequencing profiling of mouse endothelial cells in response to pulmonary arterial hypertension

Rebuttal from Sally H. Vitali

Overview: pulmonary vascular function in health and disease

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