Microenvironmental determinants of endothelial cell heterogeneity

During development, endothelial cells (ECs) undergo an extraordinary specialization by which generic capillary microcirculatory networks spanning from arteries to veins transform into patterned organotypic zonated blood vessels. These capillary ECs become specialized to support the cellular and metabolic demands of each specific organ, including supplying tissue-specific angiocrine factors that orchestrate organ development, maintenance of organ-specific functions and regeneration of injured adult organs. Here, we illustrate the mechanisms by which microenvironmental signals emanating from non-vascular niche cells induce generic ECs to acquire specific inter-organ and intra-organ functional attributes. We describe how perivascular, parenchymal and immune cells dictate vascular heterogeneity and capillary zonation, and how this system is maintained through tissue-specific signalling activated by vasculogenic and angiogenic factors and deposition of matrix components. We also discuss how perturbation of organotypic vascular niche cues lead to erasure of EC signatures, contributing to the pathogenesis of disease processes. We also describe approaches that use reconstitution of tissue-specific signatures of ECs to promote regeneration of damaged organs.