title: Inhibitory effects of recombinant RTS-jerdostatin on integrin α1β1 function during adhesion, migration and proliferation of rat aortic smooth muscle cells and angiogenesis.
abstract: Jerdostatin, a short RTS-disintegrin cloned from venom gland mRNA of Protobothrops jerdonii, selectively blocks the adhesion of α1β1 integrin to collagen IV. Integrin α1β1 is highly expressed in smooth muscle cells (SMC) surrounding small blood vessels and vascular endothelial cells. Vascular SMC adhesion, migration and proliferation are important processes during normal vascular development. Using recombinant jerdostatin we have investigated the role of the α1β1 integrin on the adhesion of vascular SMC to collagen IV, and the potential relevance of blocking this crucial component of focal adhesions as an anti-angiogenic strategy. Our results show that jerdostatin does not interact with canonical collagen-binding site on the isolated A-domain of the α1 integrin subunit. r-Jerdostatin inhibited the adhesion of RASMCs to immobilized CB3 fragment in a dose-dependent manner, triggering to round-up, retraction, and finally detachment of the cells. r-Jerdostatin did not affect the adhesion of human SMCs to CB3, presumably because the high expression of α2β1 integrin compensated for α1β1 integrin blockage by jerdostatin. r-Jerdostatin dose-dependently inhibited α1β1 integrin-dependent HUVEC tube formation. However, VEGF-driven tube formation in the matrigel assay was only completely abolished when binding of integrin α2β1 to collagen was also inhibited by the C-type lectin-like rhodocetin. As a whole, our work emphasizes the relevance of using specific inhibitors for dissecting the role of α1β1 integrin in physiological and pathological conditions.
authors.affiliation: Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Bolás
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry, University of Muenster, Waldeyerstr. 15, 48149 Muenster, Germany.
authors.forename: Flávia Figueiredo
authors.initials: FF
authors.lastname: de Rezende
authors.affiliation: Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Lorente
authors.affiliation: Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain.
authors.forename: Libia
authors.initials: L
authors.lastname: Sanz
authors.affiliation: Institute for Physiological Chemistry and Pathobiochemistry, University of Muenster, Waldeyerstr. 15, 48149 Muenster, Germany.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Eble
authors.affiliation: Instituto de Biomedicina de Valencia, CSIC, Valencia, Spain. Electronic address: jcalvete@ibv.csic.es.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Calvete
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003001:Cloning, Molecular; D003094:Collagen / Q000032:analysis; D024141:Collagen Type IV / Q000378:metabolism; D003435:Crotalid Venoms / Q000494:pharmacology; D019483:Disintegrins / Q000494:pharmacology*; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039222:Integrin alpha1beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D038982:Integrin alpha2beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007797:Laminin / Q000032:analysis; D037181:Lectins, C-Type / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D009389:Neovascularization, Pathologic / Q000473:pathology; D011509:Proteoglycans / Q000032:analysis; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology; D017819:Viperidae / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D003435:Crotalid Venoms; D019483:Disintegrins; D004338:Drug Combinations; D039222:Integrin alpha1beta1; D038982:Integrin alpha2beta1; D007797:Laminin; D037181:Lectins, C-Type; D011509:Proteoglycans; D011994:Recombinant Proteins; D014757:Viper Venoms; C554060:jerdostatin, Protobothrops jerdonii; C119730:rhodocetin; C059485:matrigel; D003094:Collagen
keywords: Angiogenesis; Cell adhesion; Jerdostatin; Recombinant RTS disintegrin; α1β1 integrin inhibitor