This Article Free Full Text Free Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Rehm, S. Articles by Boyce, R. W. Search for Related Content PubMed PubMed Citation Articles by Rehm, S. Articles by Boyce, R. W. Social Bookmarking                         What's this?

Novel Vascular Lesions in Mice Given a Non-Peptide Vitronectin Receptor Antagonist

¹ GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA 19406, USA
² Las Vegas, NV 87701, USA

Correspondence: Address correspondence to: Dr. Sabine Rehm, GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA 19406, USA; e-mail:Sabine.Rehm{at}gsk.com

Novel vascular lesions were observed in mice given an vβ3, vβ5 receptor antagonist (SB-273005) for up to 3 months. Vascular smooth muscle cell (VSMC) necrosis was observed in aorta and renal hilar arteries approximately 6 hours after dosing followed by loss of VSMC, adaptive medial thickening by VSMC hypertrophy and deposition of PAS-positive matrix and collagen. Renal hilar and arcuate arteries developed delayed and transient fibrinoid necrosis and inflammation. Vascular regeneration was not evident following drug-withdrawal after 3 days of dosing. Vascular lesions were associated with necrosis, regeneration and fibrosis of heart, kidney and spleen consistent with initial ischemic injury followed by tissue repair. VSMC toxicity was likely not related to integrin antagonism because lesions were not observed with related compounds and no vascular changes were observed in other preclinical species. In vitro studies failed to demonstrate a direct toxic effect of SB-273005 on VSMC or unique species sensitivity of murine VSMC. In conclusion, SB-273005 caused VSMC necrosis in aorta and renal arteries of mice. Lesions did not progress or recover, but there was medial hypertrophic adaptation even with continued dosing. This is considered direct species-specific VSMC toxicity of unknown mechanism and unrelated to vitronectin receptor antagonism.

Key Words: Aorta • renal artery • vascular smooth muscle • necrosis • mice

Abbreviations: EC, endothelial cell • EL, elastic laminae • DAB, 3,3 diaminobenzidine • DiI-Ac-LDL, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate-acetylated-low density lipoprotein • DMEM, Dulbecco’s Modified Eagle Media • DPBS, Dulbecco’s Phosphate Buffered Saline • H&E, hematoxylin and eosin • HRP, horseradish peroxidase • LDL, low density lipoprotein • PAS, Period acid Schiff’s reaction • PI, propidium iodide • TdT, terminal deoxynucleotidyl transferase • VSMC, vascular smooth muscle cells • w/v, weight/volume

Toxicologic Pathology, Vol. 35, No. 7, 958-971 (2007)
DOI: 10.1080/01926230701748230


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?