Abstract
The β 2 -glycoprotein I (β 2 GPI) is an endothelial cell ligand, accessible for systemic, autocrine and paracrine signaling. In vivo, β2GPI is immobilized by binding, mainly to the endothelial cell membrane heparan sulfate but also to anionic phospholipids, and functional receptors. The β 2 GPI was attributed antiangiogenic properties both in vitro and in vivo. This work was designed to evaluate the antiangiogenic effects of native, monomeric, and dimeric β 2 GPI. Monomeric as well as dimeric forms were purified from human plasma, and the native protein was obtained as a balanced mixture of both components present in human plasma. The proliferation, migration, and differentiation of Human Umbilical Vascular Endothelial Cells (HUVEC) were considered in an in vitro angiogenesis model based on tridimensional cultures and quantitative digital image processing techniques. The early events of the in vitro HUVEC growth and differentiation in the tridimensional cultures microenvironment were addressed by the morphological analysis. The morphological aspects were correlated to the cell growth, oxidative balance outcome and mitochondrial toxicity assays, leading to the evidence that non-confluent HUVEC cultures temporarily stop growing in the presence of the native protein, but remain competent to proliferate. The β2GPI monomer allowed the in vitro differentiation of the HUVECs into typical trabeculae and incomplete capillary-like tubes, along with lowering the available proliferation fraction. In opposition, the dimer rich purification fraction exposure halted cell elongation and migration, and prevented the organization of the tubular structures in tridimensional cultures, maintaining cell growth. The morphological approach was useful to attribute to β 2 GPI dimerization the cell migration inhibition modulation, which potentially leads to overcome the diminished sprouting antiangiogenic effect of the monomer fraction of the native protein.
Highlights
The β2 -glycoprotein I (β2GPI) is an endothelial cell ligand, accessible for systemic, autocrine and paracrine signaling
In vivo β2GPI molecules are immobilized by binding to heparan sulfate molecules expressed in the endothelial cell membranes, but β2GPI can bind to the anionic phospholipids enriched membranes of activated and senescent cells, and to functional receptors like ApoER2, annexin A2, TRL (Toll-like receptors) 2 e 4 and proteoglycans [21,22,23,24]
The short consensus repeat domains of β2GPI are typical of the complement control proteins superfamily (CCP), the C4 convertase activity was not documented for this protein [25]
Summary
The β2 -glycoprotein I (β2GPI) is an endothelial cell ligand, accessible for systemic, autocrine and paracrine signaling. Β2GPI is immobilized by binding, mainly to the endothelial cell membrane heparan sulfate and to anionic phospholipids, and functional receptors. The proliferation, migration, and differentiation of Human Umbilical Vascular Endothelial Cells (HUVEC) were considered in an in vitro angiogenesis model based on tridimensional cultures and quantitative digital image processing techniques. The morphological approach was useful to attribute to β2GPI dimerization the cell migration inhibition modulation, which potentially leads to overcome the diminished sprouting antiangiogenic effect of the monomer fraction of the native protein. Β2–Glycoprotein I (β2GPI), or apolipoprotein H, was recently attributed anti-angiogenic properties both in vitro and in vivo [15] These reports add new reasonable β2GPI importance on tissue regeneration and tissue proliferation to the already identified complexity of the signaling activities of β2GPI upon haemostasia and inflammation. Ioannou et al [41] reported the increased in vitro survival of endothelial cells acted by reduced β2GPI, by using thyorredoxin and NADPH
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