Smooth muscle phenotypic modulation is an early event in aortic aneurysms.
OBJECTIVE
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 alpha-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 SM22 alpha and smooth muscle alpha-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 SM22 alpha and smooth muscle alpha-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 SM22 alpha and smooth muscle alpha-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.
Ailawadi
Gorav
G
Department of Surgery, University of Virginia, Charlottesville, VA 22908, USA. gorav@virginia.edu
Moehle
Christopher W
CW
Pei
Hong
H
Walton
Sandra P
SP
Yang
Zequan
Z
Kron
Irving L
IL
Lau
Christine L
CL
Owens
Gary K
GK
D000199:Actins / Q000032:analysis; D000818:Animals; D001011:Aorta / Q000166:cytology*; D001012:Aorta, Abdominal / Q000166:cytology; D001014:Aortic Aneurysm / Q000378:metabolism / Q000473:pathology*; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology*; D010196:Pancreatic Elastase / Q000494:pharmacology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015854:Up-Regulation
D000199:Actins; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9