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Smooth Muscle Phenotypic Modulation is an Early Event in Murine Aortic Aneurysms and Human Aneurysms
Gorav Ailawadi, Sandra P. Walton, Hong Pei, Chris W. Moehle, Zequan Yang, Christine Lau, Mark C. Mochel, Irving L. Kron, Gary K. Owens; TCV Surgery, University of Virginia, Charlottesville, VA
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Objective: Vascular smooth muscle cells (SMCs) have the ability to undergo profound changes in phenotype, defined by coordinated repression of SMC marker genes and production of matrix metalloproteinases (MMPs), in models of atherosclerosis. In aneurysm development, studies have primarily focused on the role of leukocytes, while little is known of the role of SMCs. We hypothesized that SMCs undergo phenotypic modulation in experimental and human aortic aneurysms (AAs) and that his event is an early event in disease progression.
Methods: Abdominal aortas from wild type C57B6 mice (n=56) were perfused with elastase or saline (control) and harvested at 1, 3, 7 or 14 days. Aortic diameter was measured using video micrometry pre-perfusion and at harvest. Aortas were analyzed by real time-PCR and immunohistochemistry for a number of smooth muscle marker genes, including SM22α, SMα-actin, SM MHC, as well as MMP-2,-9. In complimentary experiments, human ascending aneurysmal aortas (n=10) undergoing open repair and control aorta from patients undergoing coronary artery bypass grafting (n=10) were harvested and analyzed by immunohistochemistry.
Results: Aortic diameter in elastase perfused mice was similar to saline perfused mice at 7 days (60.0 ± 9.13% versus 53.3 ± 18.3%, P=.49). At 14 days, aortic diameter was significantly larger following elastase perfusion (100 ± 9.6% versus 59.5 ± 18.9%, P=.0002). By 7 days, elastase perfused mice had significant downregulation of SM22α (0.72 ± 2.62 versus 12.19 ± 2.35, P<.0001) and SMα-actin (0.27 ± 2.84 versus 10.97 ± 1.97, P<.0001) expression compared to saline perfused animals well before the aneurysm phenotype was present. At 14 days, SM22α (1.43 ± 0.88 versus 3.26 ± 1.54, P=.05) and SMα-actin (3.73 ± 0.20 vs. 6.51 ± 1.74, P=.02) expression remained less in aneurysmal aortas. Immunohistochemistry confirmed markedly less SM22α and SMα-actin in experimental aneurysms in concert with increased MMP2,-9 staining at 7 and 14 days. Similarly, human aneurysms had less SM22α and SMα-actin and increased MMP-9 staining by immunohistochemistry compared to control aorta.
Conclusion: Experimental murine and human aneurysms demonstrate smooth muscle cell phenotypic modulation characterized by downregulation of smooth muscle marker genes and upregulation of MMPs. These events in experimental models occur early prior to aneurysm formation. Targeting SMCs to a reparative phenotype may provide a novel therapy in the treatment of aortic aneurysms.
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