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1 Medicine, Renal Research Institute, New York Medical College, Valhalla, NY, USA; Pharmacology, New York Medical College, Valhalla, NY, USA
2 The Biocomplexity Institute, Dept. Physics, Indiana University Bloomington, Bloomington, IN, USA
3 Medicine, Renal Research Institute, New York Medical College, Valhalla, NY, USA
* To whom correspondence should be addressed. E-mail: sergey_brodsky{at}nymc.edu.
Endothelium-derived microparticles emerged recently as a new marker of endothelial cell dysfunction. Increased levels of circulating microparticles have been documented in inflammatory disorders, diabetes mellitus, and many cardiovascular diseases. Perturbations of angiogenesis play an important role in the pathogenesis of these disorders. We have demonstrated previously that isolated endothelial microparticles (EMP) impair endothelial function in vitro, diminishing acetylcholine-induced vasorelaxation and nitric oxide production by rat aortic rings with a simultaneous increase in superoxide production. Herein, using the Matrigel assay of angiogenesis in vitro and a topological analysis of the capillary-like network by Human Umbilical Vein Endothelial Cells (HUVEC), we investigated the effects of EMP on the formation of the vascular network. All parameters of angiogenesis were affected by treatment for 48 hours with isolated EMP in concentrations 105/ml, but not at 103/ml or 104/ml. The effects included: decreased total capillary length (24%), decreased number of meshes (45%), decreased branching points (36%), and increased mesh area (38%). The positional and topological order indicated that EMP affect angiogenic parameters uniformly over the capillary network. Treatment with the cell-permeable SOD-mimetic MnTBAP partially or completely restored all parameters of angiogenesis affected by EMP. EMP reduced the cell proliferation rate and increased the apoptosis rate in a time- and dose dependent manner, a phenomenon which was also prevented by MnTBAP. Our data demonstrate that endothelial microparticles have considerable impact on angiogenesis in vitro and may be an important contributor to the pathogenesis of diseases that are accompanied by impaired angiogenesis.
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