Nrf2 Regulates Angiogenesis: Effect on Endothelial Cells, Bone Marrow-Derived Proangiogenic Cells and Hind Limb Ischemia

Abstract

Aims: Nuclear factor E2-related factor 2 (Nrf2), a key cytoprotective transcription factor, regulates also proangiogenic mediators, interleukin-8 and heme oxygenase-1 (HO-1). However, hitherto its role in blood vessel formation was modestly examined. Particularly, although Nrf2 was shown to affect hematopoietic stem cells, it was not tested in bone marrow-derived proangiogenic cells (PACs). Here we investigated angiogenic properties of Nrf2 in PACs, endothelial cells, and inflammation-related revascularization. Results: Treatment of endothelial cells with angiogenic cytokines increased nuclear localization of Nrf2 and induced expression of HO-1. Nrf2 activation stimulated a tube network formation, while its inhibition decreased angiogenic response of human endothelial cells, the latter effect reversed by overexpression of HO-1. Moreover, lack of Nrf2 attenuated survival, proliferation, migration, and angiogenic potential of murine PACs and affected angiogenic transcriptome in vitro. Additionally, angiogenic capacity of PAC Nrf2

Novel Faces of Heme Oxygenase-1: Mechanisms and Therapeutic Potentials

“…This is of relevance to the recent widely investigated involvement of HO-1 in stem cell differentiation [reviewed in Kozakowska et al (7)]. Both HO-1 and Nrf2, its upstream transcription factor, are necessary also for survival, proliferation, migration, and differentiation of cells previously called endothelial progenitor cells, being, in fact, rather proangiogenic monocytes, as demonstrated in the two original articles published in this Forum (3,5). We believe those works may add to several previous studies indicating the significance of HO-1 in blood vessel formation in reparative processes, which may partially depend on those cells [reviewed in this Forum: (1, 2)].…”

“…However, their progenitor/stem cell nature is currently the matter of strong debate and new data indicate that those bone marrow cells have to be considered rather as proangiogenic cells (PACs), not having the special stem cell properties. Moreover, two studies published in this Forum (3,5) indicate that PACs may not contribute (directly) to inflammation-driven revascularization. Interestingly, despite the impairment of their mobilization from bone marrow, as evidenced in the Nrf2-knockout mice, the regeneration of blood vessels after hindlimb ischemia was, in fact, accelerated in those mice in comparison with wild-type individuals (3).…”

Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 Activation in Latently Infected Endothelial Cells through SQSTM1 Phosphorylation and Interaction with Polyubiquitinated Keap1

“…We confirmed an increased level of VEGF-A expression in LTC and demonstrated that this expression was dependent on Nrf2 activation. In addition, Nrf2 participates in endothelial and cancer-associated angiogenesis (43,102,103). We therefore propose that inhibition of Nrf2 could inhibit KS-associated angiogenesis.…”

“…Furthermore, a recent study demonstrated that Nrf2 activates genes involved in the pentose phosphate pathway, which is necessary for DNA and RNA synthesis during cell proliferation (42). Finally, Nrf2 has been shown to aid in cell proliferation by augmenting PI3K/Akt signaling, inhibiting apoptosis through Bcl-2 and Bcl-xL induction, creating an angiogenic environment through HIF-1 and vascular endothelial growth factor (VEGF) expression, and participating in cell migration or invasion by altering matrix metallopeptidase 9 (MMP9) expression (42)(43)(44)(45)(46)(47).…”

Expression of NF‑E2‑related factor 2 in a rat dural arteriovenous fistula model

“…Nrf2 contributes to the protection of tissues from damage induced by the outside environment, including damage arising from inflammation, trauma, ischemia, hemorrhage and cancer (18,19). Other studies have identified an association between Nrf2 and angiogenesis (20) and it was demonstrated that the absence of Nrf2 may suppress cancer cell angiogenesis and migration in vivo and in vitro (21)(22)(23). However, the association between DAVF and Nrf2 in the pathogenesis of DAVF remains unclear.…”