Smooth muscle phenotypic modulation is an early event in aortic aneurysms

Abstract

Objectives Vascular smooth muscle cells can undergo profound changes in phenotype, defined by coordinated repression of smooth muscle cell marker genes and production of matrix metalloproteinases in response to injury. However, little is known of the role of smooth muscle cells in aortic aneurysms. We hypothesized that smooth muscle cells undergo phenotypic modulation early in the development of aortic aneurysms. Methods Abdominal aortas from C57B6 mice (n = 79) were perfused with elastase or saline (control) and harvested at 1, 3, 7, or 14 days. Aortas were analyzed by means of quantitative polymerase chain reaction and immunohistochemistry for smooth muscle cell marker genes, including SM22A, smooth muscle α-actin, and matrix metalloproteinases 2 and 9. In complimentary experiments human aneurysms (n = 10) and control aorta (n = 10) were harvested at the time of surgical intervention and analyzed. Results By 14 days, aortic diameter was larger after elastase perfusion compared with control diameter (100% ± 9.6% vs 59.5% ± 18.9%, P = .0002). At 7 days, elastase-perfused mice had a 78% and 85% reduction in SM22α and smooth muscle α-actin expression, respectively, compared with that seen in control animals well before aneurysms were present, and these values remained repressed at 14 days. Immunohistochemistry confirmed less SM22α and smooth muscle α-actin in experimental aneurysms at 14 days in concert with increased matrix metalloproteinase 2 and 9 expression at 7 and 14 days. Similarly, human aneurysms had less SM22α and smooth muscle α-actin and increased matrix metalloproteinase 2 and 9 staining, compared with control values, as determined by means of quantitative polymerase chain reaction. Conclusions Aneurysms demonstrate smooth muscle cell phenotypic modulation characterized by downregulation of smooth muscle cell marker genes and upregulation of matrix metalloproteinases. These events in experimental models occur before aneurysm formation. Targeting smooth muscle cells to a reparative phenotype might provide a novel therapy in the treatment of aortic aneurysms.

VPO1 Modulates Vascular Smooth Muscle Cell Phenotypic Switch by Activating Extracellular Signal‐regulated Kinase 1/2 (ERK 1/2) in Abdominal Aortic Aneurysms

“…During the early stages of AAA formation, VSMC undergo phenotypic switch which is characterized by downregulation of VSMC differentiation markers, such as SM‐22α, α‐SMA as well as an increase in proliferation, migration, and synthesis of extracellular matrix proteins 2, 26. In our study, we observed decreased levels of α‐SMA and SM‐22α by immunohistochemistry in human AAA and PPE‐induced AAA tissues.…”

“…VSCM phenotypic switch plays an important role in the pathogenesis of AAA 2. Thus, we examined human aorta and PPE‐induced mouse AAA model tissues for synthetic SMCs.…”

“…The phenotypic switch is characterized by VSMC dedifferentiation and migration into the neointima. VSMC phenotypic switch is an important first step in AAA formation and is marked by a loss of smooth muscle cell (SMC) gene expression, an increase in matrix metalloproteinases (MMPs) and extracellular matrix synthesis, as well as enhanced VSMC proliferation 2, 3. The precise mechanism for VSMC phenotypic switch, however, is not well understood.…”

Modulation of Kinin B2 Receptor Signaling Controls Aortic Dilatation and Rupture in the Angiotensin II–Infused Apolipoprotein E–Deficient Mouse

“…23,24 De-differentiation of VSMC to an inflammatory phenotype in response to 33 and Cnn1 deletion in differentiated VSMCs results in impaired MAPK1/3 activity and cell contractility. 34 Evidence also suggests that MAPK1/3 possesses actin-binding properties and that an intact actin cytoskeleton, degraded during apoptosis, is required for MAPK1/3 signaling.…”

“…C, Regional aortic diameter for AngII-infused ApoE −/− mice administered a B2R antagonist (B9330; white; n=12) or control (gray; n=12) determined by morphometry at euthanasia (Continued) osteopontin and osteoprotegerin were significantly lower for explants incubated in the presence of the B2R antagonist than for control explants ( There is evidence that phenotype switching in aortic smooth muscle cell (AoSMC) contributes to structural degeneration of the aortic media. 23,24 We assessed gene expression in the SRA for the SMC differentiation marker calponin 1 (CNN1) and associated mitogen-activated protein kinase 1/3 (MAPK1/3) in a subset of AngII-infused mice administered either the B2R agonist or B2R antagonist. mRNA expression for CNN1 and MAPK1/3 (relative to Gapdh) was downregulated 4-and 2-fold, respectively, in mice receiving the B2R agonist compared with control mice (Table 2).…”