title: Heme oxygenase-1 is required for angiogenic function of bone marrow-derived progenitor cells: role in therapeutic revascularization.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: 1 Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Krakow, Poland .
authors.forename: Anna
authors.initials: A
authors.lastname: Grochot-Przeczek
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kotlinowski
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kozakowska
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Starowicz
authors.forename: Jolanta
authors.initials: J
authors.lastname: Jagodzinska
authors.forename: Anna
authors.initials: A
authors.lastname: Stachurska
authors.forename: Oscar L
authors.initials: OL
authors.lastname: Volger
authors.forename: Karolina
authors.initials: K
authors.lastname: Bukowska-Strakova
authors.forename: Urszula
authors.initials: U
authors.lastname: Florczyk
authors.forename: Magdalena
authors.initials: M
authors.lastname: Tertil
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jazwa
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Szade
authors.forename: Jacek
authors.initials: J
authors.lastname: Stepniewski
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Loboda
authors.forename: Anton J G
authors.initials: AJ
authors.lastname: Horrevoets
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D057895:Haploinsufficiency; D051547:Heme Oxygenase-1 / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply; D006943:Hyperglycemia / Q000378:metabolism; D007511:Ischemia / Q000201:enzymology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D012038:Regeneration; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000502:physiology*; D059467:Transcriptome
chemical_list: D008565:Membrane Proteins; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse