Stoilova, Tsvetana Yurieva; (2025) Molecular mechanisms regulating lung vascular development. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

To mediate gas exchange after birth, the lungs are comprised of branched airways, which terminate in alveoli with an epithelial-blood vascular interface. Although blood vessels closely interact with epithelial cells in the alveolar region, it has not yet been examined whether the lung contains avascular zones akin to those that support the tissue function in other organs. During my PhD research, I found that the airway epithelium and its associated smooth muscle coat adopt an avascular state that is established during development both in mouse and human lungs. This lung architecture is maintained as epithelial branching continues and preserved into adulthood, but is disrupted in the congenital condition Down Syndrome, which is caused by Trisomy 21. My research then focussed on better understanding the molecular mechanism/s responsible for establishing the avascular zones during lung development. I found that the repulsive secreted semaphorins SEMA3C and SEMA3E are co-expressed by airway epithelium, whereas their shared receptor PLXND1 is expressed by vascular endothelium during mouse and human lung development. Thus, I have used the mouse as a model to genetically delete components of the PLXND1 pathway. Using multiplexed immunofluorescence imaging, I demonstrated that the endothelial PLXND1 deficiency causes vascular ingression into airway smooth muscle and subsequently respiratory epithelium in the embryonic and adult mouse lung. However, single SEMA3E or SEMA3C deficiency did not replicate the PLXND1 phenotype in the mouse lung, which may be explained by dispensability of the secreted semaphorins. Therefore, I used more complex genetic strategies to examine possible redundancy of semaphorin signalling and found no conclusive evidence. Overall, my results support the hypothesis that anti-angiogenic signalling through PLXND1 repels growing vascular endothelium to create avascular zones that ensure normal lung architecture throughout life. However, further work needs to establish which specific signalling molecules require PLXND1 to maintain airway zonation.

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