Heme Oxygenase-1 is Required for Angiogenic Function of Bone Marrow-derived Progenitor Cells: Role in Therapeutic Revascularization

Overview

Journal Antioxid Redox Signal

Specialty Endocrinology

Date 2013 Nov 12

PMID 24206054

Citations 33

Authors

Anna Grochot-Przeczek

Jerzy Kotlinowski

Magdalena Kozakowska

Katarzyna Starowicz

Jolanta Jagodzinska

Anna Stachurska

Oscar L Volger

Karolina Bukowska-Strakova

Urszula Florczyk

Magdalena Tertil

Agnieszka Jazwa

Krzysztof Szade

Jacek Stepniewski

Agnieszka Loboda

Anton J G Horrevoets

Jozef Dulak

Alicja Jozkowicz

Affiliations

Soon will be listed here.

Abstract

Aims: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that can be down-regulated in diabetes. Its importance for mature endothelium has been described, but its role in proangiogenic progenitors is not well known. We investigated the effect of HO-1 on the angiogenic potential of bone marrow-derived cells (BMDCs) and on blood flow recovery in ischemic muscle of diabetic mice.

Results: Lack of HO-1 decreased the number of endothelial progenitor cells (Lin(-)CD45(-)cKit(-)Sca-1(+)VEGFR-2(+)) in murine bone marrow, and inhibited the angiogenic potential of cultured BMDCs, affecting their survival under oxidative stress, proliferation, migration, formation of capillaries, and paracrine proangiogenic potential. Transcriptome analysis of HO-1(-/-) BMDCs revealed the attenuated up-regulation of proangiogenic genes in response to hypoxia. Heterozygous HO-1(+/-) diabetic mice subjected to hind limb ischemia exhibited reduced local expression of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), stromal cell-derived factor 1 (SDF-1), VEGFR-1, VEGFR-2, and CXCR-4. This was accompanied by impaired revascularization of ischemic muscle, despite a strong mobilization of bone marrow-derived proangiogenic progenitors (Sca-1(+)CXCR-4(+)) into peripheral blood. Blood flow recovery could be rescued by local injections of conditioned media harvested from BMDCs, but not by an injection of cultured BMDCs.

Innovation: This is the first report showing that HO-1 haploinsufficiency impairs tissue revascularization in diabetes and that proangiogenic in situ response, not progenitor cell mobilization, is important for blood flow recovery.

Conclusions: HO-1 is necessary for a proper proangiogenic function of BMDCs. A low level of HO-1 in hyperglycemic mice decreases restoration of perfusion in ischemic muscle, which can be rescued by a local injection of conditioned media from cultured BMDCs.

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