Abdominal Aortic Aneurysm Rupture Is Associated With Increased Medial Neovascularization and Overexpression of Proangiogenic Cytokines

Abstract

Objective-Matrix metalloproteinase (MMP) activity has been linked to abdominal aortic aneurysm (AAA) rupture.Medial neovascularization (MNV), a histopathologic characteristic of AAAs, involves proteolytic degradation of extracellular matrix by MMPs to facilitate endothelial cell migration. The role of MNV in aneurysm rupture is unknown. This study investigated whether MNV is increased in aneurysm rupture. Methods and Results-Biopsy samples from aneurysm rupture edge were compared with control biopsy samples from aneurysm wall at the level of rupture and from anterior sac in 12 ruptured AAAs. Further controls were obtained from anterior sac of 10 nonruptured AAAs. MNV, microvessel diameter, maturity index, and inflammatory infiltrate were quantified using morphometric analyses following immunohistochemistry. Expression of proangiogenic mediators was quantified using quantitative real-time-polymerase chain reaction. is expansion and rupture. Recent insights into the biological processes causing aneurysm expansion have led to translational research investigating the use of novel pharmacotherapeutic agents aimed at retarding aneurysm growth. [1][2][3] Any medical treatment of AAA must address aneurysm rupture as well as expansion. In contrast to the expansion of AAA, the biological processes causing aneurysm rupture have received little attention and current knowledge relating exclusively to the vascular biology of AAA rupture is lacking. Prospects for the development of pharmacological inhibition of aneurysm rupture therefore remain poor.Aneurysm rupture was historically considered to be a simple physical process that occurred when wall stress from the circulation exceeded the tensile strength of the aortic wall. 4 Focusing on aortic wall stress as the cause of rupture has led to the view that aneurysm rupture was regulated solely by mechanical factors. Just as the complexity of the atherosclerotic plaque has become apparent, it is now recognized that AAA rupture is a multifaceted biological process involving biochemical, cellular, and proteolytic influences in addition to biomechanical factors. 5 Proteolytic activities of MMPs have been implicated in aneurysm wall weakening and rupture. [5][6][7] Previous work have demonstrated that high levels of MMPs-8 and MMP-9 were localized to aneurysm rupture edge in humans 5 and experimental studies in rats have shown that inhibition of MMP activity by tissue inhibitor of MMP (TIMP)-1 prevented aneurysm rupture. 6 The MMP family is closely involved in the process of neovascularization 8 and play key proangiogenic roles such as the proteolytic degradation of extracellular matrix (ECM) to facilitate endothelial cell migration during angiogenesis, 9 detachment of pericytes from microvessels undergoing angiogenesis, release of ECMsequestered angiogenic growth factors, 10 exposure of cryptic proangiogenic integrin binding sites in the ECM, cleavage of vascular endothelial-cadherin endothelial cell-cell adhesions and generation of promigratory ECM fragments. 11 The medial layer o...

Microvascular COX-2/mPGES-1/EP-4 axis in human abdominal aortic aneurysm

“…The highest density of infi ltrating leukocytes in the media was in perivascular areas of these latter microvessels. The enhanced expression of EC markers in AAA was consistent with our immunochemistry observations and confi rms previous reports showing higher vascularization of AAA ( 4,5 ). After stratifi cation by the aortic diameter, the maximal transcript levels of EC markers were found in the LD group, whereas markers used to estimate leukocyte infi ltration exhibited a maximum level in the MD group.…”

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

“…Indeed, Choke et al found that biopsy samples from aneurysm rupture edge displayed increased medial neovascularization compared to the aneurysm wall at the level of rupture (region 3 cm away from the rupture edge) and from the anterior sac. Moreover, they observed that the aneurysm rupture edge displayed an increased expression of proangiogenic cytokines (αv-integrin, VEGF, VE-cadherin, MCP-1, and vimentin) [94]. Thus the focal increase in medial neovascularization in the aneurysm rupture edge, with a concomitant increase in proangiogenic expression, may contribute to the aneurysm rupture; however, further investigations are necessary to confirm this hypothesis.…”

Ultrasound in Abdominal Aortic Aneurysm

“…Neovascularization or angiogenesis is also found in relation to AAA (Herron et al, 1991;Holmes et al, 1995;Thompson et al, 1996). Choke et al (2006) found that rupture of AAA was associated with increased medial neovascularization. Assessment of neovascularization by contrast enhanced ultrasound may therefore have a significant potential for assisting in more accurate prediction of rupture.…”