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Updated: May 3, 2026
Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Cyclooxygenase-2 in endothelial and vascular smooth muscle cells restrains atherogenesis in hyperlipidemic mice
Soon Yew Tang1, James Monslow, Leslie Todd
1Institute for Translational Medicine and Therapeutics (S.Y.T., J.M., J.L., G.A.F.) and Perelman School of Medicine, Department of Animal Biology, School of Veterinary Medicine (L.T., E.P.), University of Pennsylvania, Philadelphia.
Background:
Placebo-controlled trials of nonsteroidal anti-inflammatory drugs selective for inhibition of cyclooxygenase-2 (COX-2) reveal an emergent cardiovascular hazard in patients selected for low risk of heart disease. Postnatal global deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice, a process delayed by selective enzyme deletion in macrophages.
Methods And Results:
In the present study, selective depletion of COX-2 in vascular smooth muscle cells and endothelial cells depressed biosynthesis of prostaglandin I2 and prostaglandin E2, elevated blood pressure, and accelerated atherogenesis in Ldlr knockout mice. Deletion of COX-2 in vascular smooth muscle cells and endothelial cells coincided with an increase in COX-2 expression in lesional macrophages and increased biosynthesis of thromboxane. Increased accumulation of less organized intimal collagen, laminin, α-smooth muscle actin, and matrix-rich fibrosis was also apparent in lesions of the mutants.
Conclusions:
Although atherogenesis is accelerated in global COX-2 knockouts, consistent with evidence of risk transformation during chronic nonsteroidal anti-inflammatory drug administration, this masks the contrasting effects of enzyme depletion in macrophages versus vascular smooth muscle cells and endothelial cells. Targeting delivery of COX-2 inhibitors to macrophages may conserve their efficacy while limiting cardiovascular risk.
Insights
Selective COX-2 deletion in vascular cells accelerates atherosclerosis and raises blood pressure. Targeting cyclooxygenase-2 (COX-2) inhibitors to macrophages may mitigate cardiovascular risks associated with NSAIDs.
Area of Science:
- Cardiovascular Science
- Pharmacology
- Molecular Biology
Background:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) targeting cyclooxygenase-2 (COX-2) show cardiovascular risks.
- Global COX-2 deletion accelerates atherosclerosis in mice.
- Selective COX-2 deletion in macrophages delays atherogenesis.
Purpose of the Study:
- Investigate the role of COX-2 in vascular cells versus macrophages in atherogenesis.
- Determine the impact of COX-2 depletion in specific cell types on cardiovascular parameters.
Main Methods:
- Selective postnatal deletion of COX-2 in vascular smooth muscle cells and endothelial cells in Ldlr knockout mice.
- Analysis of prostaglandin and thromboxane biosynthesis.
- Assessment of blood pressure and atherosclerotic lesion development.
Main Results:
- COX-2 depletion in vascular cells reduced prostaglandin I2 and E2 biosynthesis, increased blood pressure, and accelerated atherogenesis.
- COX-2 deletion in vascular cells led to increased COX-2 expression in lesional macrophages and elevated thromboxane.
- Lesions showed increased collagen, laminin, alpha-smooth muscle actin, and fibrosis.
Conclusions:
- COX-2 has contrasting roles in macrophages and vascular cells regarding atherogenesis.
- Global COX-2 inhibition may mask cell-specific effects observed in NSAID cardiovascular risk.
- Targeted delivery of COX-2 inhibitors to macrophages could maintain efficacy while reducing cardiovascular risk.
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