TY - JOUR T1 - Urokinase-dependent angiogenesis in vitro and diacylglycerol production are blocked by antisense oligonucleotides against the urokinase receptor. AU - Fibbi,G, AU - Caldini,R, AU - Chevanne,M, AU - Pucci,M, AU - Schiavone,N, AU - Morbidelli,L, AU - Parenti,A, AU - Granger,H J, AU - Del Rosso,M, AU - Ziche,M, PY - 1998/10/6/pubmed PY - 1998/10/6/medline PY - 1998/10/6/entrez SP - 1109 EP - 19 JF - Laboratory investigation; a journal of technical methods and pathology JO - Lab Invest VL - 78 IS - 9 N2 - The plasminogen activator system is known to play a crucial role in the angiogenesis process by modulating the adhesive properties of endothelial cells to the extracellular matrix and cell-cell interaction. In the present study, we demonstrated that the urokinase-type plasminogen activator (u-PA) induced neovascular growth in the avascular rabbit cornea and dose-dependently promoted growth, chemotaxis, and matrix invasion of cultured endothelial cells. Interaction between u-PA and its receptor appears to be mandatory for the angiogenic effect of u-PA because monoclonal antibodies anti-u-PA and anti-u-PA receptor (u-PAR) blocked the proangiogenic effects of u-PA at the endothelial cell level. We then assessed the signaling pathway activated in endothelial cells by u-PA. u-PAR activation by u-PA produced de novo synthesis of diacylglycerol (DAG) from glucose by a cytochalasin B-inhibitable mechanism, indicating the involvement of a specific glucose transporter (GLUT). Endothelial cells expressed GLUT2, whose activation was tyrosine kinase-dependent and protein kinase C (PKC)-independent. The increase of glucose uptake led to DAG production, which resulted in PKC activation/translocation. Impairment of u-PAR availability by monoclonal antibodies and by antisense oligonucleotides (aODN) against u-PAR mRNA inhibited glucose uptake, DAG neosynthesis, and PKC activation, resulting in the blockade of endothelial cell proliferation, chemotaxis, and chemoinvasion. These data suggest that u-PAR activation consequent to the binding of u-PA can be regarded as an "angiogenic switch" and disclose the possibility that an anti-u-PAR aODN strategy may efficiently target endothelial cell function to control angiogenesis in vivo. SN - 0023-6837 UR - https://www.unboundmedicine.com/medline/citation/9759655/Urokinase_dependent_angiogenesis_in_vitro_and_diacylglycerol_production_are_blocked_by_antisense_oligonucleotides_against_the_urokinase_receptor_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=9759655.ui DB - PRIME DP - Unbound Medicine ER -