Related Experiment Video
Updated: Jul 9, 2026
Venous Thrombosis Assay in a Mouse Model of Cancer
Published on: January 5, 2024
Novel vascular lesions in mice given a non-peptide vitronectin receptor antagonist
Sabine Rehm1, Roberta A Thomas, Kim S Smith
1GlaxoSmithKline, King of Prussia, PA 19406, USA. Sabine.Rehm@gsk.com
Abstract:
Novel vascular lesions were observed in mice given an alpha vbeta 3, alpha vbeta 5 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.
Insights
SB-273005 caused vascular smooth muscle cell (VSMC) necrosis in mice, leading to arterial lesions. This species-specific toxicity, unrelated to integrin antagonism, highlights a novel mechanism of vascular injury.
Area of Science:
- Toxicology
- Vascular Biology
- Pharmacology
Background:
- Integrin antagonists are investigated for therapeutic potential.
- Alpha vbeta 3 and alpha vbeta 5 receptors play roles in vascular processes.
- Understanding drug-induced vascular toxicity is crucial for safety.
Purpose of the Study:
- To investigate the vascular effects of the alpha vbeta 3, alpha vbeta 5 receptor antagonist SB-273005 in mice.
- To determine the mechanism of observed vascular lesions.
- To assess the reversibility of SB-273005-induced vascular toxicity.
Main Methods:
- Administration of SB-273005 to mice for up to 3 months.
- Histopathological examination of aorta, renal arteries, heart, kidney, and spleen.
- In vitro studies on vascular smooth muscle cells (VSMCs).
- Evaluation of vascular changes after drug withdrawal.
Main Results:
- SB-273005 induced vascular smooth muscle cell (VSMC) necrosis in mouse aorta and renal arteries.
- Lesions included medial thickening, matrix deposition, fibrinoid necrosis, and inflammation.
- No vascular regeneration was observed after drug withdrawal.
- Associated organ damage (heart, kidney, spleen) suggested ischemic injury and repair.
- In vitro studies and related compounds did not show similar toxicity, indicating species-specific effects.
Conclusions:
- SB-273005 causes direct, species-specific VSMC toxicity in mice via an unknown mechanism.
- The observed vascular lesions are unrelated to vitronectin receptor antagonism.
- The toxicity is characterized by non-progressive, non-recoverable lesions with adaptive medial changes.
