PBX transcription factors drive pulmonary vascular adaptation to birth
David J. McCulley, … , Licia Selleri, Xin Sun
David J. McCulley, … , Licia Selleri, Xin Sun
Published December 18, 2017
Citation Information: J Clin Invest. 2018;128(2):655-667. https://doi.org/10.1172/JCI93395.
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Research Article Development Genetics

PBX transcription factors drive pulmonary vascular adaptation to birth

Abstract

A critical event in the adaptation to extrauterine life is relaxation of the pulmonary vasculature at birth, allowing for a rapid increase in pulmonary blood flow that is essential for efficient gas exchange. Failure of this transition leads to pulmonary hypertension (PH), a major cause of newborn mortality associated with preterm birth, infection, hypoxia, and malformations including congenital diaphragmatic hernia (CDH). While individual vasoconstrictor and dilator genes have been identified, the coordination of their expression is not well understood. Here, we found that lung mesenchyme–specific deletion of CDH-implicated genes encoding pre–B cell leukemia transcription factors (Pbx) led to lethal PH in mice shortly after birth. Loss of Pbx genes resulted in the misexpression of both vasoconstrictors and vasodilators in multiple pathways that converge to increase phosphorylation of myosin in vascular smooth muscle (VSM) cells, causing persistent constriction. While targeting endothelin and angiotensin, which are upstream regulators that promote VSM contraction, was not effective, treatment with the Rho-kinase inhibitor Y-27632 reduced vessel constriction and PH in Pbx-mutant mice. These results demonstrate a lung-intrinsic, herniation-independent cause of PH in CDH. More broadly, our findings indicate that neonatal PH can result from perturbation of multiple pathways and suggest that targeting the downstream common effectors may be a more effective treatment for neonatal PH.

Authors

David J. McCulley, Mark D. Wienhold, Elizabeth A. Hines, Timothy A. Hacker, Allison Rogers, Ryan J. Pewowaruk, Rediet Zewdu, Naomi C. Chesler, Licia Selleri, Xin Sun

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Figure 2

Pbx1/2-CKO mice exhibit abnormal postnatal lung development, progressive cardiac hypertrophy, and PH.

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Pbx1/2-CKO mice exhibit abnormal postnatal lung development, progressiv...
(A–C) At birth, Pbx1/2-CKO mice had normal-appearing lungs and hearts relative to those of controls. (D–F) At P3, Pbx1/2-CKO mice had evidence of lung simplification compared with controls but continued to have normal-appearing heart morphology. (G–I) At P28, in the few surviving Pbx1/2-CKO mice, there was severe alveolar simplification and cardiac hypertrophy relative to controls. No consistent hemorrhaging of the heart was observed. (J) Echocardiographic measurements of the RV wall thickness (RVWT) and LV wall thickness (LVWT) revealed that RV hypertrophy was present in Pbx1/2-CKO mice relative to control mice at P10 (*P = 0.03), while the left ventricle had normal thickness (P = 0.48). (K) The PAAT/PAET ratio was used as an estimate for the pulmonary artery pressure and RV function. (L) The PAAT/PAET ratio was similar in Pbx1/2-CKO mice and controls at P3 (P = 0.45) but significantly different at P7 (**P = 0.004), P10, (***P = 0.008), and P14 (#P = 0.001). For all statistical analyses, 4 samples were included from each group. Comparisons were made using a Student’s t test. Data represent the mean ± SEM. Scale bars: 200 μm.