Smith Caroline F, Ding Kathy L, Seedorf Gregory J, Galambos Csaba, Abman Steven H
University of Colorado School of Medicine, Aurora, CO, USA.
Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO, USA.
Pediatr Res. 2025 Jun 20. doi: 10.1038/s41390-025-04127-5.
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.
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.
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.
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.
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.
T 盒转录因子 4（TBX4）中的基因变异可导致肺动脉高压（PH）；然而，疾病的发生时间和严重程度存在多种表型。先前的小鼠研究表明，种系 TBX4 基因敲除是胚胎致死性的，但关于出生后 TBX4 信号通路的破坏如何影响肺结构和 PH 仍存在知识空白。
使用一种小鼠模型，其中 TBX4 在出生后第 1 天（DOL1）失活。在 DOL21 时，评估肺功能并收集组织。评估肺泡计数（RAC）、血管密度和右心室肥厚（RVH）。检测下游肺血管生成（VEGF、KDR 和 eNOS）和炎症介质（TNF-α 和 IL-1）。
与对照组相比，TBX4 缺陷小鼠的 RAC 降低（p < 0.05）。TBX4 缺陷组的总肺阻力增加，总肺顺应性降低（p < 0.05，p < 0.01）。出生后 TBX4 缺失降低了肺血管密度（p < 0.001）并导致 RVH（p < 0.01）。TBX4 缺陷小鼠的肺促血管生成和炎症细胞因子表达降低。
出生后 TBX4 信号通路的破坏足以损害肺功能，减少肺泡和血管生长，并导致 RVH，这与肺促血管生成介质表达降低有关，但与炎症增强无关。
TBX4 功能不足是肺动脉高压（PH）的一种罕见遗传原因，其表型难以理解且多变。出生后 TBX4 的破坏足以导致幼鼠肺血管疾病并损害肺发育。虽然范围较窄，但我们推测 TBX4 破坏的延迟时间在肺表型的严重程度中起作用。TBX4 缺陷小鼠肺中的促血管生成介质（VEGF、KDR 和 eNOS）和炎症细胞因子（TNF-α 和 IL-1）下调。我们推测，更深入了解 TBX4 相关 PH 的潜在机制可能为 TBX4 疾病的管理提供新的治疗靶点。
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