The HIF1 target geneNOX2promotes angiogenesis through urotensin-II

Abstract

SummaryUrotensin-II (U-II) has been considered as one of the most potent vasoactive peptides, although its physiological and pathophysiological role is still not finally resolved. Recent evidence suggests that it promotes angiogenic responses in endothelial cells, although the underlying signalling mechanisms are unclear. Reactive oxygen species derived from NADPH oxidases are major signalling molecules in the vasculature. Because NOX2 is functional in endothelial cells, we investigated the role of the NOX2-containing NADPH oxidase in U-II-induced angiogenesis and elucidated a possible contribution of hypoxia-inducible factor-1 (HIF-1), the master regulator of hypoxic angiogenesis, in the response to U-II. We found that U-II increases angiogenesis in vitro and in vivo, and these responses were prevented by antioxidants, NOX2 knockdown and in Nox2 -/-mice. In addition, U-II-induced angiogenesis was dependent on HIF-1. Interestingly, U-II increased NOX2 transcription involving HIF-1, and chromatin immunoprecipitation confirmed NOX2 as a target gene of HIF-1. In support, NOX2 levels were greatly diminished in U-II-stimulated isolated vessels derived from mice deficient in endothelial HIF-1. Conversely, reactive oxygen species derived from NOX2 were required for U-II activation of HIF and upregulation of HIF-1. In line with this, U-II-induced upregulation of HIF-1 was absent in Nox2 -/-vessels. Collectively, these findings identified HIF-1 and NOX2 as partners acting in concert to promote angiogenesis in response to U-II. Because U-II has been found to be elevated in cardiovascular disorders and in tumour tissues, this feed-forward mechanism could be an interesting anti-angiogenic therapeutic option in these disorders.

TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy

“…Using hypoxyprobe, we found that DOX induced hypoxic stress in cardiac tissue ( Figure 2A), which in turn led to increases in the abundance of hypoxia-inducible factor 1α (HIF1α) and heme oxygenase-1 (HO-1) in mouse hearts ( Figure 2, B and C). HIF1α is known to enhance production of ROS by increasing expression of Nox2 (28), and DOX also increased the abundance of Nox2 (Figure 2, B-D). The upregulation of Nox2 expression correlated well with the reduction in heart weight caused by DOX treatment ( Figure 2D).…”

Reactive Oxygen Species Regulate Hematopoietic Stem Cell Self-Renewal, Migration and Development, As Well As Their Bone Marrow Microenvironment

“…The ROSproducing NADPH oxidase Nox-2 is a target gene of HIF-1a, and, in turn, Nox-2-derived ROS promote HIF-1a expression (12,106). Though its cross-talk with HIF-1a suggests its role in stem cell self renewal, Nox-2 activity attributes to the phagocytosis ability of myeloid cells.…”

Endothelial Deletion of Phospholipase D2 Reduces Hypoxic Response and Pathological Angiogenesis

“…37 Nox2 is a reactive oxygen species-producing enzyme known to be implicated in pathological angiogenesis. [38][39][40][41] Collectively, our findings suggest novel roles for endothelial PLD2 in regulating hypoxia-induced HIF-1α and downstream gene expression, which contribute to the cellular response of ECs to hypoxic stress and angiogenesis. This suggests that PLD2 is a modulator of EC functions during hypoxic stress and angiogenesis under pathological conditions.…”