Description
Guided by multiple signalling pathways, vascular endothelial cells (ECs) closely align with alveolar epithelium to mediate gas exchange in the lung. By contrast, the molecular and cellular mechanisms that organise airway vasculature are poorly understood. Here, we have immunostained mouse lungs to reveal that the vascular, bronchiolar smooth muscle and epithelial compartments of the airways adopt a strict zonation that is established during embryonic development when the first bronchi are formed and maintained into adulthood. Airway zonation is disrupted in mice lacking PLXND1 either globally or selectively in ECs, with angiogenic sprouting of lung capillaries first into the airway smooth muscle and then into the subepithelial space. Unexpectedly, single or combined ablation of the PLXND1 ligands with known vascular repulsive activity, SEMA3C and SEMA3E, did not compromise airway zonation to phenocopy PLXND1 loss. Nevertheless, ablating all SEMA3 signalling through PLXND1 and its co-receptors NRP1 and NRP2 caused vascular invasion of the airways, similar to the phenotype caused by PLXND1 loss, suggesting that multiple SEMA3 ligands converge on PLXND1 in an unknown mechanism. We conclude that partial redundancy of SEMA3 signalling through PLXND1 needs to be defined further to understand how airway zonation is established. Moreover, the functional significance of airway zonation needs to be investigated.
Lay Abstract
The heart functions as a pump to transport oxygenated blood from the lungs to all bodily tissues. Proper organisation of the blood vessels connecting the lungs to the heart is critical for this process, and devastating diseases like pulmonary hypertension can arise when these blood vessels do not function properly. The complex developmental mechanisms that ensure proper patterning of blood vessels in the lung at an appropriate distance from air-conducting airways have not been explored. This project investigates the role of the Plexin D1 protein in controlling blood vessel growth in the prenatal mouse lung, providing new knowledge on lung and blood vessel development, and providing new insights into how improper lung development can induce disease in humans.
| Lay Title | Investigating the biological mechanisms that control blood vessel patterning in the developing lung |
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| Role | PhD Student |