The tissue-specific transcriptional landscape underlines the involvement of endothelial cells in health and disease.

Endothelial cells (ECs) that line vascular and lymphatic vessels are being increasingly recognized as important to organ function in health and disease. ECs participate not only in the trafficking of gases, metabolites, and cells between the bloodstream and tissues but also in the angiocrine-based induction of heterogeneous parenchymal cells, which are unique to their specific tissue functions. The molecular mechanisms regulating EC heterogeneity between and within different tissues are modeled during embryogenesis and become fully established in adults. Any changes in adult tissue homeostasis induced by aging, stress conditions, and various noxae may reshape EC heterogeneity and induce specific transcriptional features that condition a functional phenotype. Heterogeneity is sustained via specific genetic programs organized through the combinatory effects of a discrete number of transcription factors (TFs) that, at the single tissue-level, constitute dynamic networks that are post-transcriptionally and epigenetically regulated. This review is focused on outlining the TF-based networks involved in EC specialization and physiological and pathological stressors thought to modify their architecture.