Endothelial cell adaptation in regeneration

Tissue-specific endothelial cells maintain organ homeostasis and instruct regeneration Endothelial cells (ECs) cover the inner wall of blood and lymph vasculature in normal and malignant tissues. It is widely appreciated that ECs are endowed with unique phenotypic, structural, functional, and angiocrine secretory attributes, generating specialized vascular subpopulations with organotypic and diseased-tissue signatures ( 1 , 2 ). To achieve this high level of organ and tumor heterogeneity, ECs have acquired malleable cellular features that allow them to adapt to normal physiological stressors and to promote tissue homeostasis and regeneration. This is exemplified during liver regeneration in which defined angiocrine (meaning EC-derived) signals from liver sinusoidal ECs initiate and resolve liver regeneration through paracrine signaling to hepatocytes. By contrast, stressed and irritated ECs maladapt to a pathological microenvironment, such as inflamed or chronically injured tissues, favoring fibrosis and tumorigenesis. Thus, EC adaptive functions have beneficial or detrimental effects in organ physiology. Understanding the molecular determinants of EC adaptability could reveal therapeutic targets to facilitate wound healing without fibrosis, combat tumorigenesis, or develop efficacious strategies for organ regeneration, long-term engraftment of bioartificial organs, and tissue transplantation.