Organ-specific heterogeneity in the endothelial cell hypoxia response is both intrinsic and reprogrammable

Endothelial cell (EC) behaviour is fundamental in control of perfusion, microvascular permeability and organ function. EC metabolism has been studied in the context of tumour vasculature, and more recently in human EC, highlighting the importance of EC metabolism and organ-specific properties as predictors of physiological behaviour, specifically in response to hypoxia.
Primary EC from murine lung (lEC), which we characterised in the context of metastatic disease and pulmonary hypertension, were compared to brain (bEC), also a continuous monolayer but from an environment with distinct physiological demands.
We found striking differences in baseline metabolism and hypoxia response (1% O2) between EC populations, but more importantly, between their metabolic properties when they were cultured in atmospheric air or in physiological O2, indicating that EC behaviour can be reprogrammed. Optimal metabolic shifts in response to hypoxia, in terms of rate and amplitude, occur in cells maintained in their respective physiological atmosphere. lEC grown at 5% O2 are unable to further induce glycolysis when transferred to 1% O2, but bEC have the highest and quickest adaptation when transferred to 1% O2 if cultured at 5% O2. In both EC, adjustment to hypoxia is compromised by hyperoxygenation. Different EC rely on different isoforms of hypoxia inducible factors (HIF) in physiological and hypoxic conditions, with levels of HIF-2a consistently higher in bEC. O2 levels significantly affected steady-state HIF levels and the cells’ ability to induce hypoxia response genes. 
These data demonstrate EC plasticity and responses are intrinsic and organ-specific, but also reprogrammable by environmental priming. Understanding the impact of stimuli to the microvasculature, whether physiological, environmental or pathological, has important implications in the prediction of microvascular behaviour in the treatment of myriad of insults, including surgery, cardiovascular or pulmonary disease, circulating factors (e.g., tumour-derived, inflammatory) and systemic therapies.