Endothelium forms a contiguous cell layer that separates blood from underlying tissue, in each of the body's organs. Cells comprising the endothelial system share common functions, including the ability to form a semipermeable barrier and an antiadhesive surface, produce vasoactive autocoids, move cells and chemical substances across their barrier, and transduce biophysical forces. These shared roles and the ability of endothelial cells (ECs) to adapt to localized environmental cues have led to the pervasive view that their behavior is dominantly controlled by local tissue environment.

Definitive evidence supports the idea that environmental stimuli adjust EC behavior on a moment-by-moment basis. However, heterogeneous endothelial behaviors are not only evident in cells from different organs, they are evident along the arterial-capillary-venule axis of a single organ and, indeed, they exist even among immediately adjacent cells. Such an incredible diversity brings into question whether environmental influences are sufficient to account for this phenotypic heterogeneity.

It has become clear that not all ECs arise from similar progenitors during development. Angiogenesis – the formation of new blood vessels from existing ones – occurs in large pulmonary blood vessels, whereas vasculogenesis – the formation of new blood vessels from blood islands – occurs within the lung's microcirculation. It is still debated as to whether these processes are fully distinct in nature, or whether they reflect interrelated developmental processes, although it is evident that multiple different mesenchymal precursor cells participate in endothelial biogenesis. It is likely that these different cells become uniquely imprinted as a part of their development. Such epigenetic modifications to chromatin, including methylation and acetylation, produce a stable cell memory that is vascular site–specific.