Effectiveness of Cyclooxygenase-2 Inhibition in Limiting Abdominal Aortic Aneurysm Progression in Mice Correlates With a Differentiated Smooth Muscle Cell Phenotype

Abstract

Abdominal aortic aneurysms (AAAs) are a chronic condition that often progress over years to produce a weakened aorta with increased susceptibility for rupture, and currently, there are no pharmacological treatments available to slow disease progression. AAA development has been characterized by increased expression of cyclooxygenase-2 (COX-2), and inactivation of COX-2 before disease initiation reduces AAA incidence in a mouse model of the disease. The current study determined the effectiveness of COX-2 inhibition on AAA progression when treatment was begun after initiation of the disease. COX-2 inhibitor treatment with celecoxib was initiated after angiotensin II-induced AAA formation in a strain of nonhyperlipidemic mice that we have previously identified as highly susceptible to AAA development. When analyzed at different time points during progression of the disease, celecoxib treatment significantly reduced the incidence and severity of AAAs. The celecoxib treatment also protected the mice from aortic rupture and death. The aneurysmal lesion displayed an altered smooth muscle cell (SMC) phenotype, whereas celecoxib treatment was associated with increased expression of differentiated SMC markers and reduced dedifferentiation marker expression during AAA progression. Maintenance of a differentiated SMC phenotype is associated with the effectiveness of COX-2 inhibition for limiting AAA progression in nonhyperlipidemic mice.

Nonsteroidal Anti-Inflammatory Drugs: A Potential Pharmacological Treatment for Intracranial Aneurysm

“…Previous research has suggested that VSMC phenotypic modulation in response to inflammatory stimuli plays a major role in the development of atherosclerosis and IA. The modulation is mediated, in part, by TNF-α [39, 40]. Animal studies of VSMCs support this idea.…”

“…Animal studies of VSMCs support this idea. VSMCs isolated from a mouse model of AAA have reduced levels of contractile phenotypic markers α-actin, desmin, and SM22α [39]. COX-2 mRNA expression in VSMCs was upregulated in both rodent and human AAA and IA studies [13, 39, 41].…”

“…VSMCs isolated from a mouse model of AAA have reduced levels of contractile phenotypic markers α-actin, desmin, and SM22α [39]. COX-2 mRNA expression in VSMCs was upregulated in both rodent and human AAA and IA studies [13, 39, 41]. Treatment of AAA mice with the selective COX-2 inhibitor celecoxib significantly decreased VSMC marker expression for differentiation [39].…”

“…COX-2 mRNA expression in VSMCs was upregulated in both rodent and human AAA and IA studies [13, 39, 41]. Treatment of AAA mice with the selective COX-2 inhibitor celecoxib significantly decreased VSMC marker expression for differentiation [39]. This decrease in phenotypic modulation in VSMCs can be attributed to a reduction in inflammation as a result of selective COX-2 inhibition, potentially through reduced TNF-α activation of NF-κB.…”

Microsomal Prostaglandin E Synthase-1 Expression by Aortic Smooth Muscle Cells Attenuates the Differentiated Phenotype

“…(5–8) In a mouse model of abdominal aortic aneurysms, we have previously determined that the effectiveness of cyclooxygenase-2 (COX-2) inhibition for limiting the progression of these aneurysms is associated with maintenance of a differentiated SMC phenotype. (9, 10) Therefore, targeting the specific COX-2-dependent pathway responsible for reducing differentiation may provide a strategy for reversing alterations to the differentiated SMC phenotype that contribute to the development of vascular pathologies.…”