Organ-specific heterogeneity in endothelial cell hypoxia response

Moritz Reiterer, Randall S. Johnson, Cristina Branco*

*Corresponding author for this work

Research output: Contribution to conferencePaperpeer-review

Abstract

The microvasculature is a heterogeneous, dynamic and versatile component of the systemic circulation, with a unique ability to locally self-regulate, to respond to organ demand and systemic stimuli, with deep effects on pathophysiological responses. In spite of the variation found among EC from different organs, it is not clear if that is intrinsically determined or a result of microenvironmental cues. We compared the hypoxia response of primary murine lung microvascular EC (lMVEC), which we have largely explored in the context of metastatic disease and pulmonary hypertension, to those of the brain (bMVEC), a network of very distinct environment and demands. Unexpectedly, our results show that bMVECs lose viability earlier and more dramatically when exposed to 1% O2 than lMVEC. This correlates with increased expression of the autophagic protein BNIP3. Hypoxic bMVECs also show metabolic dormancy, and are unresponsive to mitochondrial toxins, and only modest increases in glycolytic rate, compared to lMVECs, in keeping with mild induction of hypoxia-induced transcription factor HIF-1훼 (regulator of the switch to glycolysis). This was further seen in glucose uptake rates (glycolytic input) and extracellular acidification (glycolytic output); Overall bMVEC have reduced and attenuated hypoxia response compared to lMVEC. We investigated if these differences could be a result of environmental reprogramming, and subsequently cultured these cells at physiological oxygen levels. Cells cultured at 10% O2 (average O2 in lung) and 5% O2 (physiological O2 in brain), we found that the metabolic response to hypoxia (1% O2) was strikingly different, both between the two EC types and within the same cells cultured at different atmospheres. In all cases, higher O2 exposure elevates baseline OXPHOS and stifles the capacity to trigger glycolysis. At 10% O2 the response to hypoxia in bMVEC is still impaired compared to lMVEC, but when cultured at 5% O2, this is reversed, and bMVEC show a quick and pronounced increase in glycolytic rate when transferred to 1% O2, whereas lMVECs display no further increase in glycolysis upon 1%, suggesting 5% O2 is already hypoxic for a lMVEC. These results show that microvascular plasticity and responses are intrinsic, but to a large extent reprogrammable by environmental priming, and this knowledge is central in understanding and treating a myriad of insults to the microvasculature (surgery, wounding, any kind of circulating therapeutics, or other systemic signals).
Original languageEnglish
Publication statusPublished - 2019
EventVascular Cell Biology Gordon Research Conference: Vascular Cell Fate, Metabolism and Targeting - Ventura, United States
Duration: 20 Jan 201925 May 2020
https://www.grc.org/vascular-cell-biology-conference/2019/

Conference

ConferenceVascular Cell Biology Gordon Research Conference
Country/TerritoryUnited States
CityVentura
Period20/01/201925/05/2020
Internet address

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