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

Overview

Journal Antioxid Redox Signal

Specialty Endocrinology

Date 2013 Sep 24

PMID 24053644

Citations 48

Authors

Urszula Florczyk

Agnieszka Jazwa

Monika Maleszewska

Mateusz Mendel

Krzysztof Szade

Magdalena Kozakowska

Anna Grochot-Przeczek

Monika Viscardi

Szymon Czauderna

Karolina Bukowska-Strakova

Jerzy Kotlinowski

Alicja Jozkowicz

Agnieszka Loboda

Jozef Dulak

Affiliations

Soon will be listed here.

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(-/-) in in vivo Matrigel assay and PAC mobilization in response to hind limb ischemia of Nrf2(-/-) mice were impaired. Despite that, restoration of blood flow in Nrf2-deficient ischemic muscles was better and accompanied by increased oxidative stress and inflammatory response. Accordingly, the anti-inflammatory agent etodolac tended to diminish blood flow in the Nrf2(-/-) mice.

Innovation: Identification of a novel role of Nrf2 in angiogenic signaling of endothelial cells and PACs.

Conclusion: Nrf2 contributes to angiogenic potential of both endothelial cells and PACs; however, its deficiency increases muscle blood flow under tissue ischemia. This might suggest a proangiogenic role of inflammation in the absence of Nrf2 in vivo, concomitantly undermining the role of PACs in such conditions.

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