Nonproteolytic activation of the thrombin receptor promotes human umbilical vein endothelial cell growth but not intracellular CA2+, prostacyclin, or permeability.
Both thrombin and the synthetic tetracapeptide thrombin receptor-activating peptide (TRAP), recently described as a peptide mimicking the new amino terminus created by cleavage of the thrombin receptor, stimulated the proliferation of human umbilical vein endothelial cells (HUVEC) in culture. Although to a lesser extent, F-14, a tetradecapeptide representing the residues 365-378 of human prothrombin, also promoted HUVEC growth, thereby demonstrating that thrombin can stimulate HUVEC growth via both a proteolytic and a nonenzymatic pathway. Thrombin-TRAP, and F-14-induced HUVEC growth were inhibited by a thrombin receptor oligodeoxynucleotide antisense, showing that the growth-inducing effects of all 3 compounds were mediated through the same thrombin receptor. Thrombin and TRAP also stimulated intracellular Ca2+ increase, monolayer permeability increase, and prostacyclin release in HUVEC. None of these effects was observed with F-14 suggesting that thrombin-induced intracellular Ca2+ release, permeability increase, and prostacyclin release in HUVEC required catalytic cleavage of the receptor, whereas thrombin-induced growth might also be due to activation of the thrombin receptor through a nonproteolytic pathway.
Schaeffer
P
P
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Riera
E
E
Dupuy
E
E
Herbert
J M
JM
D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis*; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018179:Receptors, Thrombin / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D014471:Umbilical Veins / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D018179:Receptors, Thrombin; D011464:Epoprostenol; D013917:Thrombin; D002118:Calcium