Modulation of the Receptor Tyrosine Kinase TIE2/Tek Pathway by NRF2 Activation in Neurovascular Endothelial Cells

TL;DR

This paper explores how the NRF2 protein affects the TIE2/Tek pathway in brain blood vessel cells, revealing a new mechanism in blood vessel development.

Contribution

The study identifies a novel NRF2-dependent mechanism influencing TIE2/Tek levels independent of BACH1 repression.

Findings

NRF2 activation downregulates TIE2/Tek receptor expression in neurovascular endothelial cells.

TIE2/Tek repression is not mediated by BACH1 or direct transcriptional repression by NRF2.

Changes in adherens and tight junction gene expression accompany TIE2/Tek downregulation.

Abstract

The transcription factor NRF2 orchestrates diverse cellular homeostatic networks, but its role in angiogenesis remains poorly understood. Genetic and pharmacological modulation of NRF2 in mouse neuroendothelial cells altered the expression of several genes involved in endothelial biology. Among these, the TIE2/Tek receptor, essential for vascular development and integrity, was downregulated upon NRF2 activation, accompanied by changes in adherens and tight junction gene expression. Hemin treatment and knockdown revealed that TIE2/Tek repression is independent of the NRF2 repressor BACH1. mRNA stability and ChIP analyses indicated no post-transcriptional or direct transcriptional repression by NRF2. These findings suggest an alternative NRF2-dependent mechanism affecting TIE2/Tek levels and potentially influencing angiogenic regulation.

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