The endothelium is much more than the simple barrier that it was once thought to be. This single-cell layer is the maestro of blood vessel function and a complex endocrine tissue that has adapted to have specialized functions in a myriad of tissues. Endothelial dysfunction is a common feature of many cardiovascular diseases, and accumulating evidence shows that metabolic maladaptation in endothelial cells is involved in vascular functional decline. Importantly, these adaptations result in metabolic heterogeneity of endothelial cells from different tissues and, therefore, can potentially contribute to particular vascular beds being more susceptible to insult or pathologies such as diabetes mellitus.

In 1977, William Oldendorf and colleagues published the seminal study that alluded to the potential metabolic heterogeneity of endothelial cells. The investigators aimed to understand and quantify the function of the blood–brain barrier (BBB), and their research also subsequently contributed to the development of non-invasive techniques to investigate the cerebral vasculature and of nuclear medicine-based probes. This influential study used electron microscopy to assess the phenotypic structure of the endothelium as well as the mitochondrial volumes from capillaries from 13 different rat tissues. Having previously hypothesized that the maintenance of cerebral ion gradients is an energetically expensive process, Oldendorf and colleagues investigated whether the mitochondrial volume in cerebral endothelial cells differed from that of peripheral endothelial cells.