Organ-specific heterogeneity in the endothelial cell intrinsic and reprogrammable hypoxia responses

The microvasculature is a heterogeneous, dynamic and versatile component of the systemic circulation, with a unique ability to locally self-regulate and to respond to organ demand and environmental stimuli. We compared the hypoxia response of primary murine lung microvascular EC (lEC), which we have largely explored in the context of metastatic disease and pulmonary hypertension, to those of the brain (bEC), a network of very distinct physiological context and demands. We cultured these cells in normoxia (21% O2), as well as physiological oxygen levels: 10% O2 (average O2 in lung) and 5% O2 (physiological O2 in brain) and observed striking differences in baseline metabolism, as well as in their metabolic response to hypoxia (1% O2), both between the two EC types and within the same cells cultured at different atmospheres. Furthermore, we found that the hypoxia response in EC from the two tissues predominantly relied on different isoforms of the hypoxia-induced transcription factor HIF: HIF-1α in lEC and HIF-2α in bEC. Oxygen levels during cell culture significantly affected the rate of HIF-stabilisation during hypoxia, as well as its ability to induce the expression of hypoxia response genes. These results show that microvascular plasticity and responses are intrinsic to EC, but to a large extent reprogrammable by environmental priming. This knowledge is central in understanding and treating a myriad of insults to the microvasculature, such as surgery, wounding or circulating factors and therapeutics.