Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea

Author(s):Show less -

Lopes, Flavia C. M. ^[1] ; Traina, Fabiola ^{[1, 2]} ; Almeida, Camila B. ^[1] ; Leonardo, Flavia C. ^[1] ; Franco-Penteado, Carla F. ^[1] ; Garrido, Vanessa T. ^[1] ; Colella, Marina P. ^[1] ; Soares, Raquel ^[3] ; Olalla-Saad, Sara T. ^[1] ; Costa, Fernando F. ^[1] ; Conran, Nicola ^[1]

Affiliation

^[1] Univ Estadual Campinas, UNICAMP, Sch Med Sci, INCT Sangue, Hematol Ctr, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Med, Dept Internal Med, BR-14049 Ribeirao Preto - Brazil

^[3] Univ Porto, Fac Med, Dept Biochem I3S, P-4100 Oporto - Portugal

• Document type: Journal article
• Source: Haematologica; v. 100, n. 6, p. 730-739, JUN 2015.
• Web of Science Citations: 15

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 proangiogenic 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. (AU)

• FAPESP's process: 09/16334-0 - Aspects of angiogenesis in sickle cell anemia
• Grantee: Flávia Cristine Mascia Lopes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 08/57441-0 - Clinical, cellular and molecular alterations in hemoglobinopathies and other hereditary hemolytic anemias
• Grantee: Fernando Ferreira Costa
• Support Opportunities: Research Projects - Thematic Grants