Chemotactic properties of angiopoietin-1 and -2, ligands for the endothelial-specific receptor tyrosine kinase Tie2.
Angiopoietin-1 and its putative natural antagonist, angiopoietin-2, were recently isolated, and the critical role of angiopoietin-1 in embryogenic angiogenesis was demonstrated by targeted gene disruption. Specific biological effects of angiopoietin-1, however, have yet to be defined. In this study we demonstrate that angiopoietin-1, but not angiopoietin-2, is chemotactic for endothelial cells. In contrast, angiopoietin-1 as well as angiopoietin-2 exhibit no proliferative effect on endothelial cells. Excess soluble Tie2, but not Tie1 receptor, abolish the chemotactic response of endothelial cells toward angiopoietin-1. Angiopoietin-2 dose-dependently blocks directed migration toward angiopoietin-1, consistent with the role of angiopoietin-2 as a naturally occurring inhibitor of angiopoietin-1. Fibroblasts stably transfected with Tie2 receptor exhibit chemotactic responses for both angiopoietin-1 and angiopoietin-2. Fibroblasts stably expressing a transfected chimeric receptor consisting of the ectodomain of TrkC fused to the cytoplasmic domain of Tie2 also exhibit a chemotactic response to neurotrophin 3 (NT-3), a specific ligand for TrkC. Endothelial cells are shown to express angiopoietin-2 mRNA and protein, indicating the potential for autocrine activation of angiopoietin/Tie2. Finally, the demonstration that Tie2 as well as angiopoietin-1 are expressed in normal human arteries and veins suggests that the role of angiopoietin/Tie2 may extend beyond embryonic angiogenesis to maintaining integrity of the adult vasculature.
Witzenbichler
B
B
Department of Cardiovascular Research, St. Elizabeth's Medical Center of Boston, Tufts University School of Medicine, Boston, MA 02135, USA.
Maisonpierre
P C
PC
Jones
P
P
Yancopoulos
G D
GD
Isner
J M
JM
D000328:Adult; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D017209:Apoptosis / Q000187:drug effects; D015139:Blotting, Southern; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000737:chemistry; D004261:DNA Replication / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008222:Lymphokines / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042787:Receptor, TIE-2; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D008024:Ligands; D008222:Lymphokines; D008562:Membrane Glycoproteins; D011506:Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2