Abstract
Brain pericytes are important to maintain vascular integrity of the neurovascular unit under both physiological and ischemic conditions. Ischemic stroke is known to induce an inflammatory and hypoxic response due to the lack of oxygen and glucose in the brain tissue. How this early response to ischemia is molecularly regulated in pericytes is largely unknown and may be of importance for future therapeutic targets. Here we evaluate the transcriptional responses in in vitro cultured human brain pericytes after oxygen and/or glucose deprivation. Hypoxia has been widely known to stabilise the transcription factor hypoxia inducible factor 1-alpha (HIF1α) and mediate the induction of hypoxic transcriptional programs after ischemia. However, we find that the transcription factors Jun Proto-Oncogene (c-JUN), Nuclear Factor Of Kappa Light Polypeptide Gene Enhancer In B-Cells (NFκB) and signal transducer and activator of transcription 3 (STAT3) bind genes regulated after 2hours (hs) of omitted glucose and oxygen before HIF1α. Potent HIF1α responses require 6hs of hypoxia to substantiate transcriptional regulation comparable to either c-JUN or STAT3. Phosphorylated STAT3 protein is at its highest after 5 min of oxygen and glucose (OGD) deprivation, whereas maximum HIF1α stabilisation requires 120 min. We show that STAT3 regulates angiogenic and metabolic pathways before HIF1α, suggesting that HIF1α is not the initiating trans-acting factor in the response of pericytes to ischemia.
Highlights
In the brain, pericytes surround the entire microvasculature and take an important role in the neurovascular unit [1,2] by maintaining homeostasis in both, the developing and adult brain [3,4]
We present a bioinformatic analysis of the transcriptome of human brain pericytes after exposure to a) glucose deprivation, b) hypoxia (0.5–0.7% oxygen) and c) combined oxygen and glucose deprivation (OGD)
We show that hypoxic or OGD treated pericytes respond to the treatments by transcriptional programs initiated primarily by signal transducer and activator of transcription 3 (STAT3), c-JUN and NF-κB, and not HIF1α and we confirm this temporal regulation at protein level
Summary
Pericytes surround the entire microvasculature and take an important role in the neurovascular unit [1,2] by maintaining homeostasis in both, the developing and adult brain [3,4]. Pericytes respond quickly to external signals such as hypoxia, and recent data show that they secrete pro- and anti-inflammatory factors, and angiogenic molecules when exposed to oxygen or/ and glucose deprivation [5,6,7,8]. We have previously demonstrated hypoxia as a potential trigger to mobilize and recruit pericytes into tumors, where they associate with the tumor vasculature [9]. STAT3 precedes HIF1α transcriptional responses to OGD in human brain pericytes
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