title: Apolipoprotein A-I enhances proliferation of human endothelial progenitor cells and promotes angiogenesis through the cell surface ATP synthase.
abstract: BACKGROUND
  Human endothelial progenitor cells (hEPC) correspond to a subtype of stem cells which, in the presence of angiogenic stimuli, can be mobilized from bone marrow to circulation and then recruited to the damaged endothelium, where they differentiate into mature endothelial cells. High-density lipoproteins (HDL) increase the level and functionality (proliferation, migration, differentiation, angiogenesis capacity) of circulating hEPC; however, the contribution of receptors for HDL and/or apolipoprotein A-I (apoA-I), the main HDL apolipoprotein, in these effects is still unclear. On mature endothelial cells, the cell surface F1-ATP synthase has been previously characterized as a high affinity receptor of apoA-I, whereas the scavenger receptor SR-BI mainly binds with fully lipidated HDL and displays a poor affinity for lipid-free apoA-I. Furthermore, it was shown that apoA-I binding to surface ATP synthase on mature endothelial cells promotes cell proliferation, whereas inhibits apoptosis. In this work, we aimed to determine the effect of apoA-I in the proliferation and the angiogenic capacity of early hEPC, and the contribution of the cell surface ATP synthase in these events.
  
  
  RESULTS
  We first evidenced that early hEPC express the ATP synthase at the surface of nonpermeabilized cells, where it is not colocalized with MitoTracker, a mitochondria marker. ApoA-I (50 μg/mL) increases hEPC proliferation (+14.5%, p<0.001) and potentiates the effect of hEPC on a cellular model of angiogenesis, with an increase of +31% (p<0.01) in branch point counting and in tubule length. These effects of apoA-I were totally reversed in the presence of ATP synthase inhibitors, such as IF1 or oligomycin, whereas the inhibition of the HDL receptor, SR-BI, partially inhibits these events.
  
  
  CONCLUSIONS
  These results provide the first evidence that surface ATP synthase is expressed on early hEPC, where it mediates apoA-I effects in hEPC proliferation and in angiogenesis. This knowledge could be helpful for future investigations focused on the regulation of the number and functionality of these cells and in the development of new therapies for the treatment of diseases, such as cardiovascular disease.
authors.affiliation: Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.
authors.forename: Valentina
authors.initials: V
authors.lastname: González-Pecchi
authors.affiliation: Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.
authors.forename: Sara
authors.initials: S
authors.lastname: Valdés
authors.affiliation: INSERM, UMR1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse 31432, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Pons
authors.affiliation: Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.
authors.forename: Paula
authors.initials: P
authors.lastname: Honorato
authors.affiliation: INSERM, UMR1048, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse 31432, France.
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Martinez
authors.affiliation: Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.
authors.forename: Liliana
authors.initials: L
authors.lastname: Lamperti
authors.affiliation: Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Aguayo
authors.affiliation: Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile. Electronic address: cradojkovic@udec.cl.
authors.forename: Claudia
authors.initials: C
authors.lastname: Radojkovic
mesh_terms: D000328:Adult; D016632:Apolipoprotein A-I / Q000502:physiology*; D017209:Apoptosis; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism*; D066026:Endothelial Progenitor Cells / Q000378:metabolism; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D018919:Neovascularization, Physiologic; D006180:Proton-Translocating ATPases / Q000378:metabolism*; D018110:Receptors, Lipoprotein / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D055815:Young Adult
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D018110:Receptors, Lipoprotein; C031616:high density lipoprotein receptors; D006180:Proton-Translocating ATPases
keywords: Angiogenesis; Apolipoprotein A-I; Endothelial progenitor cells; Proliferation; Surface ATP synthase