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Novel Vascular Lesions in Mice Given a Non-Peptide Vitronectin Receptor Antagonist
Novel vascular lesions were observed in mice given an αvβ3, αvβ5 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 V...
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Published in: | Toxicologic pathology 2007-12, Vol.35 (7), p.958-971 |
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creator | Rehm, Sabine Thomas, Roberta A. Smith, Kim S. Mirabile, Rosanna C. Gales, Tracy L. Eustis, Scot L. Boyce, Rogely W. |
description | Novel vascular lesions were observed in mice given an αvβ3, αvβ5 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. |
doi_str_mv | 10.1080/01926230701748230 |
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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. 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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.</description><subject>Animals</subject><subject>Aorta - drug effects</subject><subject>Aorta - pathology</subject><subject>Apoptosis - drug effects</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Female</subject><subject>Heart - drug effects</subject><subject>Immunohistochemistry</subject><subject>Integrin alphaVbeta3 - antagonists & inhibitors</subject><subject>Kidney - drug effects</subject><subject>Kidney - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Microscopy, Electron</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - pathology</subject><subject>Pyridines - toxicity</subject><subject>Renal Artery - drug effects</subject><subject>Renal Artery - pathology</subject><subject>Spleen - drug effects</subject><subject>Spleen - pathology</subject><issn>0192-6233</issn><issn>1533-1601</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><recordid>eNp9kEFLAzEQhYMoWqs_wIvk5mlrZrPJpsdStAq1StFelzQ7LZFtUpPdgv_elBY8CJ5mmPfNY-YRcgNsAEyxewbDXOaclQzKQqXmhPRAcJ6BZHBKens9SwC_IJcxfjIGCgp2Ti5AsaFiRd4j85nfYUMXOpqu0YFOMVrvIrWOvliDdGJ36KimM--yN9y2tka6sG3wDk2boDmaNPWBjlyr197Z2F6Rs5VuIl4fa598PD68j5-y6evkeTyaZqYA3maF0TJdVEA9lJiXBTNyiVJwpkUS5DJXBpSqUUAp6pURQqgkF3UupeQKDe-Tu4PvNvivDmNbbWw02DTaoe9iVQoBnJdQJhIOpAk-xoCrahvsRofvCli1T7L6k2TauT26d8sN1r8bx-gSMDgAUa-x-vRdcOnbfxx_ADjBeXw</recordid><startdate>200712</startdate><enddate>200712</enddate><creator>Rehm, Sabine</creator><creator>Thomas, Roberta A.</creator><creator>Smith, Kim S.</creator><creator>Mirabile, Rosanna C.</creator><creator>Gales, Tracy L.</creator><creator>Eustis, Scot L.</creator><creator>Boyce, Rogely W.</creator><general>SAGE Publications</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>C1K</scope></search><sort><creationdate>200712</creationdate><title>Novel Vascular Lesions in Mice Given a Non-Peptide Vitronectin Receptor Antagonist</title><author>Rehm, Sabine ; 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subjects | Animals Aorta - drug effects Aorta - pathology Apoptosis - drug effects Cell Adhesion - drug effects Cell Survival - drug effects Cells, Cultured Female Heart - drug effects Immunohistochemistry Integrin alphaVbeta3 - antagonists & inhibitors Kidney - drug effects Kidney - pathology Male Mice Mice, Inbred ICR Microscopy, Electron Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - pathology Pyridines - toxicity Renal Artery - drug effects Renal Artery - pathology Spleen - drug effects Spleen - pathology |
title | Novel Vascular Lesions in Mice Given a Non-Peptide Vitronectin Receptor Antagonist |
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