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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

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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 6

PBX plays a central role in perinatal pulmonary VSM relaxation.

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PBX plays a central role in perinatal pulmonary VSM relaxation.
(A) Norm...
(A) Normal perinatal pulmonary VSM relaxation is the result of increased expression of factors that promote vasodilation and of decreased expression of factors that promote vasoconstriction. (B) Loss of PBX results in the failure of normal transition, with decreased expression of vasodilators and increased expression of vasoconstrictors causing high PVR and lethal PH. (C) Treatment with Y-27632 restores pulmonary VSM relaxation and reduces PH.
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