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 1

PBX1 is expressed in the lung mesenchyme.

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PBX1 is expressed in the lung mesenchyme. (A and B) PBX1 was broadly exp...
(A and B) PBX1 was broadly expressed throughout the lung mesenchyme at E12.5 through early postnatal stages. (C–F) PBX1 was expressed in multiple cell types in the lung mesenchyme including vWF-stained vascular endothelium, SM22-stained VSM, PDGFRα-GFP–stained alveolar myofibroblasts, and ADRP-stained lipofibroblasts. (G and H) Tbx4-Cre had broad activity in the lung mesenchyme when crossed with a green fluorescent reporter and overlapped with PBX1 expression in SM22-stained alveolar myofibroblasts (indicated by asterisks) and VSM (indicated by arrows). (I) Using Tbx4Cre to delete Pbx1 resulted in widespread loss of PBX1 in the mutant mouse as compared with the control lung mesenchyme in B. Within the mutant, there was a more complete loss of PBX1 in the alveolar mesenchyme (AM) than in the peribronchial mesenchyme adjacent to central airways (Ai) and vessels (Ve). (J–L) Pbx1/2-CKO mice lacked PBX1 expression in SM22-stained VSM and PDGFRα-GFP–labeled alveolar myofibroblasts but retained PBX1 expression in vWF-stained endothelium. Scale bars: 100 μm.