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-activ ating peptide (TRAP), recently described as a peptide mimicking the ne w amino terminus created by cleavage of the thrombin receptor, stimula ted the proliferation of human umbilical vein endothelial cells (HUVEC ) in culture. Although to a lesser extent, F-14, a tetradecapeptide re presenting the residues 365-378 of human prothrombin, also promoted HU VEC growth, thereby demonstrating that thrombin can stimulate HUVEC gr owth via both a proteolytic and nonenzymatic pathway. Thrombin-TRAP-, and F-14-induced HUVEC growth were inhibited by a thrombin receptor ol igodeoxynucleotide 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, monolay er permeability increase, and prostacyclin release in HUVEC. None of t hese effects was observed with F-14, suggesting that thrombin-induced intracellular Ca2+ release, permeability increase, and prostacyclin re lease in HUVEC required catalytic cleavage of the receptor, whereas th rombin-induced growth might also be due to activation of the thrombin receptor through a nonproteolytic pathway. (C) 1997 Elsevier Science I nc.