The Role of Apoptosis in the Coarctation-Induced Abdominal Aortic Aneurysm in a Porcine Model

Abstract

Aneurysms an abnormal expansion of the vascular wall occur in 4-8% of the population over 65 years old Abdominal aortic aneurysm (AAA) is the most common aneurysm that usually occurs between the renal arteries and the aortic bifurcation The mortality rate of AAA reaches 90% when ruptured and presents a significant clinical problem AAA is characterized by chronic inflammation extracellular matrix degradation and loss of vascular smooth muscle cells (VSMCs) In human AAA tissues VSMC density decreases while apoptotic cells increase compared with normal aorta Therefore apoptosis of VSMCs may play an important role in aneurysm formation Our laboratory developed a coarctation-induced degenerative AAA model by surgically narrowing an infrarenal abdominal aorta (AA) segment in Lanyu mini pigs In this model AAA was formed in the aortic segment distal to coarctation at 12 weeks post-coarctation We hypothesized that prolonged coarctation of abdominal aorta induces apoptosis of vascular cells that participate in AAA formation An infrarenal AA segment was wrapped with an ePTFE Teflon strip for 4 weeks (4w) 8 weeks (8w) or 12 weeks (12w) Histological analysis showed that aortic lumen perimeter markedly increased in the distal AA compared to the suprarenal AA at 12w post-coarctation In the distal AA fragmentation and degradation of elastic lamellae in the media increased with time and collagen remodeling was detected Cellular apoptosis examined with terminal transferase dUTP nick end labeling (TUNEL) assay showed that TUNEL-positive cells in the media increased at 4w and gradually decreased to basal levels at 12w post-coarctation Interestingly TUNEL-positive cells were abundant in the intima and adventitia Double immunofluorescence staining was used to identify cell types which underwent apoptosis during AAA formation Apoptotic rate of endothelial cells in the intima appeared high in all groups except for the 12w post-coarctation whereas endothelial apoptosis in the vasa vasorum of the adventitia appeared to increase at 4w post-coarctation Apoptosis of VSMC in the media appeared focal and was mainly detected at 4w post-coarctation In addition in the sub-endothelial intima apoptosis was detected in S100A4-positive cells which may represent phenotypically modified VSMCs at 4w and 8w post-coarctation In contrast apoptotic rate of macrophages and fibroblasts both were distributed in the adventitia was low Using immunoblotting analysis no change in active caspase-3 and LC3 was detected in the distal AA segment In summary prolonged coarctation of the abdominal aorta induces apoptosis of endothelial cells in the intima and vasa vasorum and VSMCs in the intima and media of the distal AA segment which may contribute to coarctation-induced AAA formation

Date of Award	2014 Aug 30
Original language	English
Supervisor	Meei-Jyh Jiang (Supervisor)