Endothelial Heterogeneity in Pulmonary Hypertension

Abstract

The lung endothelium is essential for maintaining normal lung structure and plays a key role in gas exchange, barrier function, angiogenesis, vascular tone, and inflammation regulation. The advent of single-cell RNA sequencing has revealed the unique heterogeneity of pulmonary endothelial cells (ECs) in their function, morphology, and localization. Pulmonary hypertension (PH) is a progressive vascular disorder marked by elevated pulmonary arterial pressure and vascular remodeling. Central to its pathogenesis is EC dysfunction, and emerging evidence highlights EC heterogeneity in driving the complexity of PH. The distinct lung endothelial subpopulations exhibit diverse molecular signatures and functional responses under PH. A complete picture of how these different subpopulations contribute to vascular remodeling of PH is critical to identify novel therapeutic opportunities. This brief review summarizes recent insights into EC dysfunction in PH, focusing on the role of specialized EC subsets and novel therapeutic strategies targeting EC dysfunction. We highlight the integration of cutting-edge technologies in understanding how endothelial heterogeneity shapes the trajectory of PH and opens new avenues for future therapeutic innovations.

Keywords: capillaries; endothelial cells; hypertension, pulmonary; pulmonary arterial hypertension; vascular remodeling.

Figure 1.. Pulmonary EC dysregulation in PH.

EC dysregulation in PH has been extensively reviewed elsewhere^,,. Briefly, environmental stressors, mechanical forces, and genetic perturbations activate abnormal inflammatory, metabolic, and epigenetic responses in AECs. These changes promote a proliferative, anti-apoptotic, and EndoMT phenotype that contributes to vascular remodeling in PH. Hypoxia induces autophagy in capillary (Cap) ECs while promoting AEC proliferation, resulting in AECs replacement of Cap ECs during vascular remodeling. General Cap cells (gCaps or Cap1) have also been reported to reprogram into AECs in SuHx and Egln1-deficient mouse model, a process regulated by the HIF-2α/Notch4 axis. By contrast, intratracheal delivery of adeno-associated virus-Nr2f2 promotes gCaps differentiation into EphB4⁺ PVECs, suppressing angiogenesis and vascular development, thereby mitigating SuHx-induced PH in mouse models. In ACDMPV-PH, FOXF1 deficiency impairs gCap differentiation into aCap (Cap2) and compromises aCap survival through reduced VEGFA-KDR signaling. In pulmonary veins, group 2 PH is associated with elevated shear stress that activates Rho/Rho-kinase and EndoMT signaling pathways, disrupting PVECs tight junctions and promoting vascular remodeling. SVECs may serve as a compensatory contributor to pulmonary perfusion under obstructed conditions in PH. The solid lines represent causal connections, while the dotted lines indicate potential connections. The arrows leading to the panel borders suggest that the pathway contributes to the development of PH.