Background Genetic variants in T-box transcription factor 4 (TBX4) cause pulmonary hypertension (PH); however, there are diverse phenotypes with respect to the timing and severity of disease. Previous mouse studies demonstrated that germline TBX4 knockout is embryonic lethal, but knowledge gaps exist in how postnatal disruption of TBX4 signaling affects lung structure and PH. Methods A mouse model was used in which TBX4 was inactivated on day of life (DOL) 1. On DOL21, lung function was evaluated, and tissue was collected. Radial alveolar counts (RAC), vessel density, and right ventricular hypertrophy (RVH) were assessed. Downstream lung angiogenic (VEGF, KDR, and eNOS) and inflammatory mediators (TNF-a and IL-1) were measured. Results TBX4-deficient mice exhibited decreased RAC compared to controls (p < 0.05). Total lung resistance was increased, and total lung compliance was reduced in the TBX4-deficient group (p < 0.05, p < 0.01). Postnatal TBX4 deletion reduced lung vessel density (p < 0.001) and caused RVH (p < 0.01). Lung pro-angiogenic and inflammatory cytokine expression was reduced in TBX4-deficient mice. Conclusion Postnatal disruption of TBX4 signaling is sufficient to impair lung function, reduce alveolar and vascular growth, and cause RVH, which are associated with decreased lung expression of pro-angiogenic mediators but not enhanced inflammation. Impact <UnorderedList Mark="Bullet"> <ItemContent> TBX4 insufficiency is a rare genetic cause of pulmonary hypertension (PH) with poorly understood, variable phenotypes. </ItemContent> <ItemContent> Postnatal disruption of TBX4 is sufficient to cause pulmonary vascular disease and impair lung development in infant mice. Although narrower in scope, we hypothesize that the late timing of TBX4 disruption plays a role in the severity of the lung phenotype. </ItemContent> <ItemContent> Pro-angiogenic mediators (VEGF, KDR, and eNOS) and inflammatory cytokines (TNF-a and IL-1) are downregulated in the lungs of TBX4-deficient mice. </ItemContent> <ItemContent> We speculate that greater insight into the mechanisms underlying TBX4-related PH may provide novel therapeutic targets for the management of TBX4 disease. </ItemContent> </UnorderedList>

Postnatally induced TBX4 insufficiency confers pulmonary hypertension and impairs lung development in infant mice

期刊论文
发表日期：

2025年6月20日

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Caroline F. Smith,
Kathy L. Ding,
Gregory J. Seedorf,
Csaba Galambos,
Steven H. Abman

摘要

Background

Genetic variants in T-box transcription factor 4 (TBX4) cause pulmonary hypertension (PH); however, there are diverse phenotypes with respect to the timing and severity of disease. Previous mouse studies demonstrated that germline TBX4 knockout is embryonic lethal, but knowledge gaps exist in how postnatal disruption of TBX4 signaling affects lung structure and PH.

Methods

A mouse model was used in which TBX4 was inactivated on day of life (DOL) 1. On DOL21, lung function was evaluated, and tissue was collected. Radial alveolar counts (RAC), vessel density, and right ventricular hypertrophy (RVH) were assessed. Downstream lung angiogenic (VEGF, KDR, and eNOS) and inflammatory mediators (TNF-a and IL-1) were measured.

Results

TBX4-deficient mice exhibited decreased RAC compared to controls (p < 0.05). Total lung resistance was increased, and total lung compliance was reduced in the TBX4-deficient group (p < 0.05, p < 0.01). Postnatal TBX4 deletion reduced lung vessel density (p < 0.001) and caused RVH (p < 0.01). Lung pro-angiogenic and inflammatory cytokine expression was reduced in TBX4-deficient mice.

Conclusion

Postnatal disruption of TBX4 signaling is sufficient to impair lung function, reduce alveolar and vascular growth, and cause RVH, which are associated with decreased lung expression of pro-angiogenic mediators but not enhanced inflammation.

Impact

TBX4 insufficiency is a rare genetic cause of pulmonary hypertension (PH) with poorly understood, variable phenotypes.

Postnatal disruption of TBX4 is sufficient to cause pulmonary vascular disease and impair lung development in infant mice. Although narrower in scope, we hypothesize that the late timing of TBX4 disruption plays a role in the severity of the lung phenotype.

Pro-angiogenic mediators (VEGF, KDR, and eNOS) and inflammatory cytokines (TNF-a and IL-1) are downregulated in the lungs of TBX4-deficient mice.

We speculate that greater insight into the mechanisms underlying TBX4-related PH may provide novel therapeutic targets for the management of TBX4 disease.