Caroline F. Smith, Kathy L. Ding, Gregory J. Seedorf, Csaba Galambos, Steven H. Abman
University of Colorado School of Medicine.
United States
Pediatric Research
Pediatr Res 2025;
DOI: 10.1038/s41390-025-04127-5
Abstract
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.
Category
Class III. Pulmonary Hypertension Associated with Developmental Diseases of the Lung
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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