Excessive Postnatal Smooth Muscle Differentiation in a Lung Specific Model of TBX4-related Pulmonary Hypertension

Lea C. Steffes; Kaylie A. Chiles; Sehar R. Masud; Aleen Rahman; Madeline Dawson; Csaba Galambos; Maya E. Kumar; Ripla Arora

doi:10.1172/jci.insight.194251

Excessive Postnatal Smooth Muscle Differentiation in a Lung Specific Model of TBX4-related Pulmonary Hypertension

Lea C. Steffes,¹ Kaylie A. Chiles,² Sehar R. Masud,¹ Aleen Rahman,¹ Madeline Dawson,² Csaba Galambos,³ Maya E. Kumar,¹ and Ripla Arora⁴

Published April 27, 2026 - More info

View PDF

Abstract

Heterozygous TBX4 variants are the second most common genetic cause of pediatric pulmonary hypertension (PH), yet mechanisms underlying TBX4-related lung disease remain poorly understood. This study developed a lung mesenchyme-specific Tbx4 loss-of-function (Tbx4cKO) mouse model that bypasses embryonic lethality to investigate this condition. Adult Tbx4cKO mice demonstrated significantly impaired pulmonary flow acceleration consistent with PH. Three-dimensional analysis of embryonic lungs revealed reduced lobe volumes and decreased distance between pleural edges and muscularized vessels. In adult Tbx4cKO lungs, we identified extensive vascular remodeling characterized by medial thickening and the extension of muscularized arteries into normally non-muscularized subpleural parenchymal zones. Contrary to previous reports suggesting vascular simplification, three-dimensional analysis demonstrated an elaborated pulmonary artery (PA) tree in addition to pathologic wall muscularization. Depletion of a single Tbx5 allele in addition to both Tbx4 alleles exacerbated histologic phenotypes with worsened right ventricular dilation. This model also demonstrated dysregulated airway smooth muscle patterning and prominent subpleural smooth muscle bands, similar to those in human TBX4 syndrome. We identify TBX4 as a critical regulator of smooth muscle differentiation and patterning across multiple lung compartments. Our model recapitulates key features of human TBX4 syndrome and identifies dysregulated smooth muscle differentiation as a potential future therapeutic target.

Excessive Postnatal Smooth Muscle Differentiation in a Lung Specific Model of TBX4-related Pulmonary Hypertension

Lea C. Steffes,¹ Kaylie A. Chiles,² Sehar R. Masud,¹ Aleen Rahman,¹ Madeline Dawson,² Csaba Galambos,³ Maya E. Kumar,¹ and Ripla Arora⁴

Article tools

Metrics

Go to

Excessive Postnatal Smooth Muscle Differentiation in a Lung Specific Model of TBX4-related Pulmonary Hypertension

Lea C. Steffes,1 Kaylie A. Chiles,2 Sehar R. Masud,1 Aleen Rahman,1 Madeline Dawson,2 Csaba Galambos,3 Maya E. Kumar,1 and Ripla Arora4

Article tools

Metrics

Go to

Sign up for email alerts

Lea C. Steffes,¹ Kaylie A. Chiles,² Sehar R. Masud,¹ Aleen Rahman,¹ Madeline Dawson,² Csaba Galambos,³ Maya E. Kumar,¹ and Ripla Arora⁴