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Published on: January 16, 2013
Postnatally induced TBX4 insufficiency confers pulmonary hypertension and impairs lung development in infant mice
Caroline F Smith1, Kathy L Ding2, Gregory J Seedorf3
1University of Colorado School of Medicine, Aurora, CO, USA. caroline.smith@cuanschutz.edu.
Insights
Postnatal disruption of T-box transcription factor 4 (TBX4) impairs lung development and function, leading to pulmonary hypertension in mice. This study reveals TBX4 insufficiency causes reduced alveolar and vascular growth, not inflammation.
Area of Science:
- Genetics
- Pulmonary Medicine
- Developmental Biology
Background:
- Genetic variants in T-box transcription factor 4 (TBX4) are linked to pulmonary hypertension (PH) with variable disease severity.
- While germline TBX4 knockout is lethal, the effects of postnatal TBX4 signaling disruption on lung development and PH remain unclear.
Purpose of the Study:
- To investigate the impact of postnatal TBX4 signaling disruption on lung structure, function, and pulmonary hypertension in a mouse model.
- To explore the downstream effects on angiogenic and inflammatory mediators.
Main Methods:
- TBX4 was inactivated in mice on postnatal day 1.
- Lung function, radial alveolar counts (RAC), vessel density, and right ventricular hypertrophy (RVH) were assessed on day 21.
- Expression of angiogenic (VEGF, KDR, eNOS) and inflammatory (TNF-a, IL-1) mediators was measured.
Main Results:
- TBX4-deficient mice showed significantly reduced RAC, increased lung resistance, and decreased lung compliance.
- Postnatal TBX4 deletion led to diminished lung vessel density and caused RVH.
- Expression of pro-angiogenic mediators was reduced, while inflammatory cytokine expression was not significantly enhanced.
Conclusions:
- Postnatal disruption of TBX4 signaling is sufficient to impede lung development, impair lung function, and induce RVH in infant mice.
- The observed lung phenotype is associated with reduced expression of pro-angiogenic factors.
- Understanding TBX4 mechanisms may offer therapeutic targets for TBX4-related PH.
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.
