Novel Populations of Lung Capillary Endothelial Cells and Their Functional Significance

Abstract

The role of the lung's microcirculation and capillary endothelial cells in normal physiology and the pathobiology of pulmonary diseases is unequivocally vital. The recent discovery of molecularly distinct aerocytes and general capillary (gCaps) endothelial cells by single-cell transcriptomics (scRNAseq) advanced the field in understanding microcirculatory milieu and cellular communications. However, increasing evidence from different groups indicated the possibility of more heterogenic structures of lung capillaries. Therefore, we investigated enriched lung endothelial cells by scRNAseq and identified five novel populations of gCaps with distinct molecular signatures and roles. Our analysis suggests that two populations of gCaps that express Scn7a(Na+) and Clic4(Cl−) ion transporters form the arterial-to-vein zonation and establish the capillary barrier. We also discovered and named mitotically-active "root" cells (Flot1+) on the interface between arterial, Scn7a+, and Clic4 + endothelium, responsible for the regeneration and repair of the adjacent endothelial populations. Furthermore, the transition of gCaps to a vein requires a venous-capillary endothelium expressing Lingo2. Finally, gCaps detached from the zonation represent a high level of Fabp4, other metabolically active genes, and tip-cell markers showing angiogenesis-regulating capacity. The discovery of these populations will translate into a better understanding of the involvement of capillary phenotypes and their communications in lung disease pathogenesis.

Angiogenesis Redux: An Overall Protective Role of VEGF/KDR Signaling in the Microvasculature in Pulmonary Arterial Hypertension

“…In the era of single-cell transcriptomics, a growing number of pulmonary vascular EC subtypes has been identified, [29][30][31] some of which may harbor differential functions of Flk1 or VEGF signaling in the pulmonary microcirculation. Some of the various EC subsets identified include pulmonary artery ECs, capillary ECs (aerocytes and general capillary ECs), pulmonary venous ECs, and systemic venous ECs, 29,30 with general capillary ECs thought to be composed of 5 subgroups with distinct functions.…”

“…Some of the various EC subsets identified include pulmonary artery ECs, capillary ECs (aerocytes and general capillary ECs), pulmonary venous ECs, and systemic venous ECs, 29,30 with general capillary ECs thought to be composed of 5 subgroups with distinct functions. 31 With the advent of newer EC subpopulation-targeting genetic tools, the role of VEGFR2 signaling may be further elucidated with respect to these EC subpopulations. Similarly, a direct comparison of the roles of VEGFR2 with that of putative decoy receptor VEGFR1 or lymphatic EC receptor VEGFR3 (VEGF receptor 3) by gene ablation might help to resolve some of the remaining controversies and unknowns in the function of VEGF signaling in PAH.…”