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

被引：107

作者：

Florczyk, Urszula ^{[1
]}

Jazwa, Agnieszka ^{[1
]}

Maleszewska, Monika ^{[1
]}

Mendel, Mateusz ^{[1
]}

Szade, Krzysztof ^{[1
,2
]}

Kozakowska, Magdalena ^{[1
,2
]}

Grochot-Przeczek, Anna ^{[1
,2
]}

Viscardi, Monika ^{[1
]}

Czauderna, Szymon ^{[1
]}

Bukowska-Strakova, Karolina ^{[1
,2
]}

Kotlinowski, Jerzy ^{[1
]}

Jozkowicz, Alicja ^{[1
]}

Loboda, Agnieszka ^{[1
]}

Dulak, Jozef ^{[1
]}

机构：

[1] Jagiellonian Univ, Dept Med Biotechnol, Fac Biochem Biophys & Biotechnol, PL-30387 Krakow, Poland

[2] Jagiellonian Ctr Expt Therapeut, Krakow, Poland

来源：

ANTIOXIDANTS & REDOX SIGNALING | 2014年 / 20卷 / 11期

关键词：

NITRIC-OXIDE SYNTHASE; PROGENITOR CELLS; HEME OXYGENASE; TRANSCRIPTION FACTOR; OXIDATIVE STRESS; HIF-1; INDUCTION; IL-8; EXPRESSION; GROWTH-FACTOR; NEOVASCULARIZATION; MOBILIZATION;

D O I：

10.1089/ars.2013.5219

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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. Antioxid. Redox Signal. 20, 1693-1708.

引用

页码：1693 / 1708

页数：16

共 56 条

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