Piecing together the alveolar-capillary unit: arterial-venous capillary polarization

Pulmonary capillary endothelial cells (ECs) form a highly specialized vascular interface that sustains gas exchange and organismal survival across species. Recent advances in single-cell transcriptomics and lineage tracing have revealed substantial heterogeneity within the pulmonary endothelium, redefining traditional views of capillary structure and function. In the adult lung, two major capillary populations, general capillary ECs (CAP1) and aerocyte capillary ECs (CAP2), have been identified, with CAP1 cells increasingly recognized as a heterogeneous and functionally diverse compartment that includes EC progenitors and reparative subpopulations. Emerging datasets further demonstrate arterial-venous polarization within the capillary bed and reveal gradients of gene expression that extend from macrovascular arteries and veins into the alveolar microvasculature. Within this polarized CAP1 landscape, several transcriptionally distinct EC subsets exhibit enhanced angiogenic potential and may contribute to EC regeneration during injury. This review synthesizes current knowledge of pulmonary capillary EC heterogeneity, emphasizing arterial-venous polarization of the capillary network, and the identification of reparative EC progenitors within the CAP1 population. We highlight emerging technologies, including EC enrichment strategies, transcriptomics, and epigenomic profiling, that are beginning to resolve rare EC states and functional niches within the alveolar microvasculature. A deeper understanding of capillary EC diversity and lineage dynamics will be essential for identifying therapeutic targets aimed at restoring vascular stability, promoting regenerative angiogenesis, and preserving gas exchange in aging lungs and chronic lung diseases. Ethics: No Human or Animal subjects. Publicly available data sets: Gene Expression Omnibus (GEO)/NCBI: Human ILD data: GSE227136; Mouse data: GSE242065.