Induction and suppression of interferon-inducible protein (IP)-10 in reperfused myocardial infarcts may regulate angiogenesis

Regulation of angiogenesis is dependent on the net biological balance between expression of angiogenic and angiostatic molecules in the injured tissue. Using a canine model of myocardial ischemia/reperfusion, we demonstrated that expression of the angiostatic chemokine interferon-inducible protein (IP-10) peaked at 1-3 h of reperfusion and virtually disappeared by 24 h of reperfusion. IP-10 mRNA and protein were localized in the venular endothelium during early reperfusion of ischemic myocardial segments and were not detected after 24 h. Endothelial cell proliferation was first noted after 24 h of reperfusion, and alphav beta3 expressing neovessels were seen after 72-120 h of reperfusion, suggesting that neovascularization began only when IP-10 expression was markedly reduced. Isolated canine venular endothelial cells expressed high levels of IP-10 and IL-8 mRNA upon stimulation with tumor necrosis factor (TNF) -alpha and endotoxin. Transforming growth factor (TGF) -beta, but not interleukin (IL) -10, decreased TNF-alpha-mediated IP-10 expression in canine endothelial cells. In contrast, TNF-alpha-mediated IL-8 induction was not affected by incubation with IL-10 or TGF-beta. Induction of angiostatic factors, such as IP-10, in the first hours following injury may be important in inhibiting premature neovessel formation, until the appropriate supportive matrix is present. IP-10 down-regulation by active TGF-beta may mediate the onset of neovascularization by allowing unopposed VEGF- and IL-8-mediated angiogenic activity.