title: Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea.
abstract: As hypoxia-induced inflammatory angiogenesis may contribute to the manifestations of sickle cell disease, we compared the angiogenic molecular profiles of plasma from sickle cell disease individuals and correlated these with in vitro endothelial cell-mediated angiogenesis-stimulating activity and in vivo neovascularization. Bioplex demonstrated that plasma from patients with steady-state sickle cell anemia contained elevated concentrations of pro-angiogenic factors (angiopoietin-1, basic fibroblast growth factor, vascular endothelial growth factor, vascular endothelial growth factor-D and placental growth factor) and displayed potent pro-angiogenic activity, significantly increasing endothelial cell proliferation, migration and capillary-like structure formation. In vivo neovascularization of Matrigel plugs was significantly greater in sickle cell disease mice than in non-sickle cell disease mice, consistent with an up-regulation of angiogenesis in the disease. In plasma from patients with hemoglobin SC disease without proliferative retinopathy, anti-angiogenic endostatin and thrombospondin-2 were significantly elevated. In contrast, plasma from hemoglobin SC individuals with proliferative retinopathy had a pro-angiogenic profile and more significant effects on endothelial cell proliferation and capillary formation than plasma from patients without retinopathy. Hydroxyurea therapy was associated with significant reductions in plasma angiogenic factors and inhibition of endothelial cell-mediated angiogenic mechanisms and neovascularization. Thus, individuals with sickle cell anemia or hemoglobin SC disease with retinopathy present a highly angiogenic circulating milieu, capable of stimulating key endothelial cell-mediated angiogenic mechanisms. Combination anti-angiogenic therapy to prevent the progression of unregulated neovascularization and associated manifestations in sickle cell disease, such as pulmonary hypertension, may be indicated; furthermore, the benefits and drawbacks of the potent anti-angiogenic effects of hydroxyurea should be clarified.
authors.affiliation: INCT de Sangue, Hematology Center, School of Medical Science, University of Campinas - UNICAMP, São Paulo, Brazil.
authors.forename: Flavia C M
authors.initials: FC
authors.lastname: Lopes
authors.affiliation: INCT de Sangue, Hematology Center, School of Medical Science, University of Campinas - UNICAMP, São Paulo, Brazil Department of Internal Medicine, University of São Paulo at Riberão Preto Medical School, Riberão Preto, Brazil.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Traina
authors.affiliation: INCT de Sangue, Hematology Center, School of Medical Science, University of Campinas - UNICAMP, São Paulo, Brazil.
authors.forename: Camila B
authors.initials: CB
authors.lastname: Almeida
authors.affiliation: INCT de Sangue, Hematology Center, School of Medical Science, University of Campinas - UNICAMP, São Paulo, Brazil.
authors.forename: Flavia C
authors.initials: FC
authors.lastname: Leonardo
authors.affiliation: INCT de Sangue, Hematology Center, School of Medical Science, University of Campinas - UNICAMP, São Paulo, Brazil.
authors.forename: Carla F
authors.initials: CF
authors.lastname: Franco-Penteado
authors.affiliation: INCT de Sangue, Hematology Center, School of Medical Science, University of Campinas - UNICAMP, São Paulo, Brazil.
authors.forename: Vanessa T
authors.initials: VT
authors.lastname: Garrido
authors.affiliation: INCT de Sangue, Hematology Center, School of Medical Science, University of Campinas - UNICAMP, São Paulo, Brazil.
authors.forename: Marina P
authors.initials: MP
authors.lastname: Colella
authors.affiliation: Department of Biochemistry (I3S), Faculty of Medicine, University of Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Soares
authors.affiliation: INCT de Sangue, Hematology Center, School of Medical Science, University of Campinas - UNICAMP, São Paulo, Brazil.
authors.forename: Sara T
authors.initials: ST
authors.lastname: Olalla-Saad
authors.affiliation: INCT de Sangue, Hematology Center, School of Medical Science, University of Campinas - UNICAMP, São Paulo, Brazil.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Costa
authors.affiliation: INCT de Sangue, Hematology Center, School of Medical Science, University of Campinas - UNICAMP, São Paulo, Brazil conran@unicamp.br.
authors.forename: Nicola
authors.initials: N
authors.lastname: Conran
mesh_terms: D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000188:drug therapy*; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology* / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000097:blood* / Q000188:drug therapy; D055815:Young Adult
chemical_list: D000986:Antisickling Agents; D006918:Hydroxyurea