Inhibition of endothelial cell migration, intercellular communication, andvascular tube formation by thromboxane A(2)

The eicosanoid thromboxane A(2) (TXA(2)) is released by activated platelets , monocytes, and the vessel wall and interacts with high affinity receptors expressed in several tissues including endothelium. Whether TXA(2) might a lter endothelial migration and tube formation, two determinants of angiogen esis, is unknown. Thus, we investigated the effect of the TXA(2) mimetic [1 S-(1 alpha,2 beta(5Z)),3 alpha(1E,3R),4 alpha]-7-[3-(3-hydroxy-4-(4'-iodoph enoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5'-heptenoic acid (IBOP) on human endothelial cell (HEC) migration and angiogenesis in vitro. IBOP stimulation inhibited REC migration by 50% and in vitro capillary formation by 75%. These effects of IBOP were time- and concentration-dependent with an IC50 of 25 nM. IBOP did not affect integrin expression or cytoskeletal m orphology of HEC. Since gap junction-mediated intercellular communication i ncreases in migrating HEC, we determined whether IBOP might inhibit couplin g or connexin expression in HEC. IBOP reduced the passage of microinjected dyes between HEC by 50%, and the effects of IBOP on migration and tube form ation were mimicked by the gap junction inhibitor 18 beta-glycyrrhetinic ac id (1 mu M) with a similar time course and efficacy. IBOP (24 h) did not af fect the expression or phosphorylation of connexin 43 in whole HEC lysates. Immunohistologic examination of HEC suggested that IBOP may impair functio nal coupling by altering the cellular distribution of gap junctions, leadin g to increased connexin 43 internalization. Thus, this finding that TXA(2) mimetics can prevent HEC migration and tube formation, possibly by impairin g intercellular communication, suggests that antagonizing TXA(2) signaling might enhance vascularization of ischemic tissue.