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Delta-like 4 is required for pulmonary vascular arborization and alveolarization in the developing lung
Sheng Xia, … , Thomas Korfhagen, Venkatesh Sampath
Sheng Xia, … , Thomas Korfhagen, Venkatesh Sampath
Published April 8, 2021
Citation Information: JCI Insight. 2021;6(7):e134170. https://doi.org/10.1172/jci.insight.134170.
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Research Article Pulmonology Vascular biology

Delta-like 4 is required for pulmonary vascular arborization and alveolarization in the developing lung

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Abstract

The molecular mechanisms by which endothelial cells (ECs) regulate pulmonary vascularization and contribute to alveolar epithelial cell development during lung morphogenesis remain unknown. We tested the hypothesis that delta-like 4 (DLL4), an EC Notch ligand, is critical for alveolarization by combining lung mapping and functional studies in human tissue and DLL4-haploinsufficient mice (Dll4+/lacz). DLL4 expressed in a PECAM-restricted manner in capillaries, arteries, and the alveolar septum from the canalicular to alveolar stage in mice and humans. Dll4 haploinsufficiency resulted in exuberant, nondirectional vascular patterning at E17.5 and P6, followed by smaller capillaries and fewer intermediate blood vessels at P14. Vascular defects coincided with polarization of lung EC expression toward JAG1-NICD-HES1 signature and decreased tip cell-like (Car4) markers. Dll4+/lacZ mice had impaired terminal bronchiole development at the canalicular stage and impaired alveolarization upon lung maturity. We discovered that alveolar type I cell (Aqp5) markers progressively decreased in Dll4+/lacZ mice after birth. Moreover, in human lung EC, DLL4 deficiency programmed a hypersprouting angiogenic phenotype cell autonomously. In conclusion, DLL4 is expressed from the canalicular to alveolar stage in mice and humans, and Dll4 haploinsufficiency programs dysmorphic microvascularization, impairing alveolarization. Our study reveals an obligate role for DLL4-regulated angiogenesis in distal lung morphogenesis.

Authors

Sheng Xia, Heather L. Menden, Nick Townley, Sherry M. Mabry, Jeffrey Johnston, Michael F. Nyp, Daniel P. Heruth, Thomas Korfhagen, Venkatesh Sampath

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Figure 1

DLL4 is expressed from the canalicular through alveolar stage of mouse and human lung development.

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DLL4 is expressed from the canalicular through alveolar stage of mouse a...
(A) DLL4 (red), PECAM (green), and nucleus (DAPI, blue) staining on mouse lung samples at E17.5, P2, P7, P14, and P28. E17.5 represents canalicular stage; P2 represents saccular stage; and P7, P14, and P28 represent early, middle, and completed alveolar stage. (B) DLL4 (red) and PECAM (green) staining on human lung slides at 22, 27, 36, and 39 gestational age weeks (22, 27, and 36/39 week represent human canalicular, saccular, and early alveolar stages). Scale bars: 10 μm. n = 4 per group.

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