Abstract 96: Aberrations in the Sonic Hedgehog/Notch Signaling Pathway in Abdominal Aortic Aneurysms
Objectives: The molecular mechanisms leading to the development of Adnominal Aortic Aneurysms (AAA) remain poorly understood. Vascular Smooth Muscle Cells (VSMCs) are fundamental to maintaining a healthy arterial wall and changes in VSMC phenotype may be pivotal to aneurysm development. We have recently determined a role for a Hedgehog (Hh)/Notch signaling cascade in regulating adult VSMC phenotype. The aim of this study was to investigate Hh/Notch signaling components in aneurysmal and non-aneurysmal aorta. As crosstalk between Notch and Transforming Growth Factor Beta (TGFβ) has been postulated we also investigated expression of this growth factor.
Methods: Tissue samples were obtained from aneurysmal and non-aneurysmal segments of the aortic wall of at least 5 patients with suitable anatomy undergoing open repair of infrarenal AAA. All samples analyzed were paired from the same patient with aneurysmal and non-aneurysmal specimens. Protein and mRNA expression levels were determined by western blot analysis and quantitative Real-time PCR respectively.
Results: SHh, Notch 1 and 3 IC protein expression was decreased by at least 50% in aneurysmal tissue when compared to non-aneurysmal tissue. In addition, SHh mRNA expression was also decreased by 65%, while there was a decrease in Dll4, Notch 1 and Notch 3 by 66%, 57% and 54% respectively. In contrast, aneurysmal tissue had significantly increased expression of TGFβ and MMP9. TGFB protein and mRNA expression was significantly increased by 5.45±2.13 and 2.5±.2 fold respectively in aneurysmal tissue when compared to non-aneurysmal tissue. Furthermore, MMP9 mRNA expression was significantly increased by 4.7±1.6 fold. In parallel experiments, SMC alpha actin protein expression was significantly decreased by 90% in aneurysmal tissue when compared to non-aneurysmal tissue.
Conclusion: These results suggest that SHH/Notch and TGFβ signaling is altered in aneurysmal tissue, compared with non-aneurysmal tissue. Changes in these signaling pathways and resulting changes in VSMC phenotype may play a role in the development of AAA.
- © 2012 by American Heart Association, Inc.