Inhibition of endothelial cell migration, intercellular communication, and vascular 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 alter endothelial migration and tube formation, two determinants of angiogenesis, is unknown. Thus, we investigated the effect of the TXA(2) mimetic [1S-(1alpha, 2beta(5Z),3alpha(1E,3R), 4alpha]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-o xab icyclo- [2.2.1]heptan-2-yl]-5'-heptenoic acid (IBOP) on human endothelial cell (HEC) migration and angiogenesis in vitro. IBOP stimulation inhibited HEC migration by 50% and in vitro capillary formation by 75%. These effects of IBOP were time- and concentration-dependent with an IC(50) of 25 nM. IBOP did not affect integrin expression or cytoskeletal morphology of HEC. Since gap junction-mediated intercellular communication increases in migrating HEC, we determined whether IBOP might inhibit coupling 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 formation were mimicked by the gap junction inhibitor 18beta-glycyrrhetinic acid (1 microM) with a similar time course and efficacy. IBOP (24 h) did not affect the expression or phosphorylation of connexin 43 in whole HEC lysates. Immunohistologic examination of HEC suggested that IBOP may impair functional coupling by altering the cellular distribution of gap junctions, leading to increased connexin 43 internalization. Thus, this finding that TXA(2) mimetics can prevent HEC migration and tube formation, possibly by impairing intercellular communication, suggests that antagonizing TXA(2) signaling might enhance vascularization of ischemic tissue.
Ashton
A W
AW
Department of Medicine (Cardiology), the Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA. ashton@aecom.yu.edu
Yokota
R
R
John
G
G
Zhao
S
S
Suadicani
S O
SO
Spray
D C
DC
Ware
J A
JA
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects / Q000502:physiology*; D002450:Cell Communication / Q000187:drug effects*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D018031:Connexin 43 / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000032:analysis; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D013928:Thromboxane A2 / Q000494:pharmacology*; D014471:Umbilical Veins; D014945:Wound Healing / Q000187:drug effects
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018031:Connexin 43; D005231:Fatty Acids, Unsaturated; D016023:Integrins; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; D013928:Thromboxane A2; D002118:Calcium