Angiostatin inhibits extracellular HIV-Tat-induced inflammatory angiogenesis.
The HIV-Tat protein can be released extracellularly where it is able to recruit leukocytes and induce angiogenesis. These activities are mediated by the direct interaction of Tat with VEGFR2 on endothelial cells and chemokine receptors on leukocytes. We have recently shown that angiostatin, an anti-angiogenic peptide fragment of plasminogen, is able to inhibit the recruitment of neutrophils induced by bacterial fMLP and alpha chemokines both in vitro and in vivo. In vivo this was associated with an inhibition of the angiogenic response by angiostatin. These observations suggested that angiostatin could be a suitable inhibitor of Tat-induced angiogenesis, as it acts on both endothelial and neutrophil at the same time. In vitro, chemotaxis assays demonstrated that angiostatin inhibited Tat-induced chemotaxis of neutrophils with an inverse bell shaped profile. In vivo the injection of matrigel plugs containing Tat or its chemokine-like peptide (CysL24-51) caused the infiltration of neutrophils and a strong angiogenic response. Angiostatin completely blocked this inflammatory response, inhibiting the recruitment of inflammatory and endothelial cells inside the implant. Taken together, these results indicate that angiostatin can act as an inhibitor of both endothelial and neutrophil recruitment. As these cell types are also the targets of extracellularly released Tat, angiostatin could be used to contrast Tat-associated vasculopathies.
Benelli
Roberto
R
Molecular Biology Laboratory, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Morini
Monica
M
Brigati
Claudio
C
Noonan
Douglas M
DM
Albini
Adriana
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D043168:Angiostatins; D003094:Collagen / Q000502:physiology; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D006678:HIV / Q000472:pathogenicity*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D007797:Laminin / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D010958:Plasminogen / Q000494:pharmacology* / Q000627:therapeutic use; D011509:Proteoglycans / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D015696:Gene Products, tat; D007797:Laminin; D010446:Peptide Fragments; D011509:Proteoglycans; D054322:tat Gene Products, Human Immunodeficiency Virus; C059485:matrigel; D043168:Angiostatins; D010958:Plasminogen; D003094:Collagen