title: Genetic and pharmacologic inactivation of cannabinoid CB1 receptor inhibits angiogenesis.
abstract: In this study we investigated the role of CB1 receptor signaling in angiogenesis and the therapeutic exploitation of CB1 inactivation as an antiangiogenic strategy. We started from the observation that CB1 receptor expression is induced during angiogenesis and that the endocannabinoid anandamide stimulated bFGF-induced angiogenesis in the nanomolar physiologic range. To define the functional involvement of CB1 receptor signaling during angiogenesis, 2 different strategies have been carried out: siRNA-mediated knockdown and pharmacologic antagonism of CB1 receptors. CB1 receptors inactivation resulted in the inhibition of bFGF-induced endothelial proliferation, migration, and capillary-like tube formation, through prosurvival and migratory pathways involving ERK, Akt, FAK, JNK, Rho, and MMP-2. To corroborate the potential therapeutic exploitation of CB1 blockade as an antiangiogenic strategy, we performed in vivo assays founding that CB1 blockade was able to inhibit bFGF-induced neovascular growth in the rabbit cornea assay. A relevant finding was the ability to reduce ocular pathologic neo-vascularization in mouse oxygen-induced retinopathy. These results demonstrate that CB1 signaling participates to the proliferative response elicited by proangiogenic growth factors in angiogenesis and that for this reason CB1 receptor could represent a novel target for the treatment of diseases where excessive neoangiogenesis is the underlying pathology.
authors: Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano, Italy.
authors: Simona
authors: S
authors: Pisanti
authors: Paola
authors: P
authors: Picardi
authors: Lucia
authors: L
authors: Prota
authors: Maria Chiara
authors: MC
authors: Proto
authors: Chiara
authors: C
authors: Laezza
authors: Paul G
authors: PG
authors: McGuire
authors: Lucia
authors: L
authors: Morbidelli
authors: Patrizia
authors: P
authors: Gazzerro
authors: Marina
authors: M
authors: Ziche
authors: Arup
authors: A
authors: Das
authors: Maurizio
authors: M
authors: Bifulco
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007231:Infant, Newborn; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D011817:Rabbits; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D012178:Retinopathy of Prematurity / Q000188:drug therapy; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D016222:Fibroblast Growth Factor 2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2