Lung endothelial cell heterogeneity in health and pulmonary vascular disease

Abstract

Lung endothelial cells (ECs) are essential for maintaining organ function and homeostasis. Despite sharing some common features with ECs from organ systems, lung ECs exhibit significant heterogeneity in morphology, function, and gene expression. This heterogeneity is increasingly recognized as a key contributor to the development of pulmonary diseases like pulmonary hypertension (PH). In this mini-review, we explore the evolving understanding of lung EC heterogeneity, particularly through the lens of single-cell RNA sequencing (scRNA-seq) technologies. These advances have provided unprecedented insights into the diverse EC subpopulations, their specific roles, and the disturbances in their homeostatic functions that contribute to PH pathogenesis. In particular, these studies identified novel and functionally distinct cell types such as aerocytes and general capillary ECs that are critical for maintaining lung function in health and disease. In addition, multiple novel pathways and mechanisms have been identified that contribute to aberrant pulmonary vascular remodeling in PH. Emerging techniques like single-nucleus RNA sequencing and spatial transcriptomics have further pushed the field forward by discovering novel disease mediators. As research continues to leverage these advanced techniques, the field is poised to uncover novel EC subtypes and disease mechanisms, paving the way for new therapeutic targets in PH and other lung diseases.

Keywords: angiogenesis; proliferation; pulmonary circulation; pulmonary hypertension; single-cell RNA sequencing.

Figure 1.. Endothelial cell type distribution and their most relevant gene signatures in the human lung.

Note the distinct spatial distribution of EC types and distinguishing gene signatures. Aerocytes, specialized in gas exchange, are located in the thin-walled portions of the alveoli. General capillary cells are located in the septal regions of the alveolus. Systemic venous ECs are predominantly located in the visceral pleura and large airways. Pulmonary arterial and pulmonary venous ECs are present in the airways forming the broncho vascular bundle and in the lung parenchyma. Most relevant gene signatures are shown in boxes. Previously established, general endothelial functions and genes are not listed for clarity. Please see table 1 for exhaustive list of gene signatures.

Fig. 2:. Upregulated pathways in endothelial cells in pulmonary arterial hypertension identified via recent single cell RNA sequencing and spatial transcriptomics studies.

*HIF2α/Notch4 signaling has been identified as a driver of distal arterialization in PAH.