Am J Physiol Lung Cell Mol Physiol. 2019 Jul 3. doi: 10.1152/ajplung.00104.2018. [Epub ahead of print]
https://www.ncbi.nlm.nih.gov/pubmed/31268349
Inhibition of retinoic acid signaling induces aberrant pericyte coverage and differentiation resulting in vascular defects in congenital diaphragmatic hernia.
Kool HM1, Burgisser PE1, Edel GG1, De Kleer I2, Boerema-de Munck A3, de Laat I1, Chrifi I4, Cheng C5, van Cappellen WA6, Kremers GJ6, Tibboel D7, Rottier RJ8.
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Abstract
The mortality and morbidity of patients with congenital diaphragmatic hernia(CDH) is primarily caused by treatment-resistant, persistent pulmonary hypertension. Structural vascular changes, exemplified by extensive muscularization, are already present early in gestation, but the origin of these abnormalities is unknown. Understanding the origin of the vascular defects is important to improve treatment modalities. Here, we show that the distribution of pericytes is different and may thereby potentially initiate the vascular pathology in CDH. Transient inhibition of retinoic acid signaling early during pregnancy, the basis of the CDH mouse model, led to an increase in the number of pericytes, thereby affected the angiogenic potential of pericytes in the fetuses. Pericytes of CDH lungs showed reduced proliferation and an increased ACTA2 expression, which indicates that these pericytes are more contractile than in control lung pericytes. This resulted in increased pericyte coverage of pulmonary vessels and reduced expansion of the capillary bed, the earliest pathological sign of the structural changes in CDH. Furthermore, the pericytes had reduced and altered collagen IV deposition in CDH, pointing to a loss of basal membrane integrity between pericytes and endothelial cells. Inhibition of RA signaling in vitro resulted in reduced migration of pericytes, reduced angiogenesis and loss of collagen IV expression. Importantly, we confirmed our findings in lungs of human CDH patient samples. In summary, inhibition of retinoic acid signaling affects the lung pericyte population, leading to increased contractility, reduced pulmonary angiogenesis and aberrant lung development as observed in CDH.
KEYWORDS:
angiogenesis; animal model of human disease; congenital diaphragmatic hernia; lung development; pulmonary hypertensionPMID: 31268349 DOI: 10.1152/ajplung.00104.2018
