Connective tissue proteinases and inhibitors in abdominal aortic aneurysms. Involvement of the vasa vasorum in the pathogenesis of aortic aneurysms.

Herron, G. Scott; Unemori, Elaine; Wong, Marco D.; Rapp, Joseph H.; Hibbs, M H; Stoney, Ronald J.

doi:10.1161/01.atv.11.6.1667

Cited by 145 publications

(81 citation statements)

References 44 publications

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“…5 Immunolocalization studies have indicated that some MMPs produced in aneurysms were associated with proliferative microvessels. 13 Collectively, these earlier observations together with findings from the present study implicated a potential pathway for aneurysm rupture involving angiogenesis and its elaboration of MMPs. The localized elevation of these proteases in areas of active neovascularization may have a role in focal extracellular matrix degradation and AAA rupture.…”

Section: Discussionsupporting

confidence: 78%

“…11 The medial layer of the infrarenal human abdominal aorta, unlike the thoracic aorta, is not normally supplied by microvessels from the adventitial vasa vasorum. 12 Neovascularization of the medial layer is a consistent feature of established AAAs; 13 however, the role of this pathological angiogenic response in aneurysm rupture has never been investigated. 14,15 As pathological neovascularization occurs in close spatial proximity to the collagen and elastin network of the aortic media, the expression of MMPs during such angiogenic response may lead to proteolytic disruption and degradation of aortic media.…”

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confidence: 99%

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

Choke

Thompson

Dawson

et al. 2006

ATVB

136

117

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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...

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Section: Discussionsupporting

confidence: 78%

mentioning

confidence: 99%

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

Choke

Thompson

Dawson

et al. 2006

ATVB

136

117

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“…4,22 Recently, MMP-12 was reported to be prominently expressed by aneurysm-infiltrating macrophages within the media of human AAA. 5 The roles of MMP-9 and MMP-12 in the pathogenesis of AAA have been investigated in a mouse model of elastase-induced aneurysm.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice

Wang¹,

Martin-McNulty²,

Freay

et al. 2001

The American Journal of Pathology

111

125

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Urokinase-type plasminogen activator (uPA) is increased in human abdominal aortic aneurysm (AAA).Chronic infusion of angiotensin II (Ang II) results in AAA in apolipoprotein E-deficient mice. We tested the hypothesis that Ang II infusion results in an elevation of uPA expression contributing to aneurysm formation. Ang II or vehicle was infused by osmotic pumps into apoE-KO mice. All mice treated with Ang II developed a localized expansion of the suprarenal aorta (75% increase in outer diameter), accompanied by an elevation of blood pressure (22 mmHg), compared to the vehicle-treated group. Histological examination of the dilated aortic segment revealed similarities to human AAA including focal elastin fragmentation, macrophage infiltration, and intravascular hemorrhage. Ang II treatment resulted in a 13-fold increase in the expression of uPA mRNA in the AAA segment in contrast to a twofold increase in the atherosclerotic aortic arch. Increased uPA protein was detected in the abdominal aorta as early as 10 days after Ang II infusion before significant aorta expansion. Thus, Ang II infusion results in macrophage infiltration, increased uPA activity, and aneurysm formation in the abdominal aorta of apoE-KO mice. These data are consistent with a causal role for uPA in the pathogenesis of AAA. Abdominal aortic aneurysm (AAA) is a chronic degenerative disease characterized by segmental weakening and dilation of the vascular wall. Recent estimates indicate that the prevalence of AAA is 4 to 9% in adults older than 65 years of age and is known to be associated with atherosclerosis, aging, hypertension, and cigarette smoking. Continued tissue remodeling results in silent expansion of the AAA with an increased risk of spontaneous rupture. Currently the only available treatments for AAAs are surgical resection and replacement or, more recently, insertion of an endovascular stent. The etiology of AAA is unclear. The extracellular matrix plays an essential role in maintaining the integrity of the vascular wall. Elastin and collagen fibers are the major components of this extracellular matrix. Both plasmin and matrix metalloproteinases (MMPs) are capable of degrading extracellular matrix, including collagen, elastin, and fibrin. Urokinase-type plasminogen activator (uPA) hydrolyzes plasminogen to form plasmin, which in turn activates MMPs. The in vivo activity of uPA is also regulated by local concentrations of its major inhibitor, PAI-1. Biochemical studies have demonstrated increased proteolytic activity in the aortic wall of AAA. Schneiderman and colleagues 1 showed that uPA mRNA as well as the tissue-type plasminogen activator (tPA), co-localized with infiltrating macrophages, is significantly increased in human AAA. Increased activities of MMP-2, -3, -9, and -12 in AAA have also been reported. [2][3][4][5] Atherosclerotic aortic lesions from high-cholesterol diet-fed apoE-KO mice show fragmentation of the elastic lamellae and rupture of the media resulting in pseudomicroaneurysm formation. These pathological changes are ...

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“…The vessels of the vasa vasorum form the pathways by which inflammatory cells access the aortic intima and media. 10 Medial neovascularization and decreased vascular smooth muscle cells also characterize AAA lesions. The intraluminal thrombus may contribute to the process by causing a functional hypoxia at the luminal intima and inner media, thus inducing subsequent neovascularization and inflammation.…”

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confidence: 99%

Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms

Shimizu

Mitchell

Libby

2006

ATVB

568

478

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Abstract-Expansion and rupture of abdominal aortic aneurysms (AAA) result in high morbidity and mortality rates. Like stenotic atherosclerotic lesions, AAA accumulate inflammatory cells, but usually exhibit much more extensive medial damage. Leukocyte recruitment and expression of pro-inflammatory Th1 cytokines typically characterize early atherogenesis of any kind, and modulation of inflammatory mediators mutes atheroma formation in mice. 1 However, the mechanistic differences between stenotic and aneurysmal manifestations of atherosclerosis remain unexplained. We recently showed that aortic allografts deficient in interferon-␥ (IFN-␥) signaling developed AAA correlating with skewed Th2 cytokine environments, suggesting important regulatory roles for Th1/Th2 cytokine balance in modulating matrix remodeling and important implications for the pathophysiology of aortic aneurysm and atherosclerosis. Key Words: aortic aneurysm Ⅲ atherosclerosis Ⅲ cytokine Ⅲ pathogenesis Ⅲ T-lymphocytes Ⅲ transplantation A ortic aneurysms are permanent and localized aortic dilations defined as having diameters 1.5-times greater than normal (ie, Ͼ3 cm diameter for abdominal aortic aneurysms [AAA]). In comparison, the term aortic ectasia describes localized aortic enlargement Ͻ1.5-times normal diameter. 2 Although most aneurysms remain asymptomatic and undiagnosed, risk of rupture increases dramatically when diameters exceed 5.5 cm. Despite surgical advances, the prognosis of ruptured AAA remains poor, and the overall mortality remains high (80% to 90%). 3 Although surgical or endovascular repair constitutes the major therapeutic options for AAA Ͼ5.5 cm, such invasive procedures provide no therapeutic advantage for AAA Ͻ5.5 cm diameter.Most AAA develop below the renal arteries and end above the bifurcation of the iliac arteries; they typically exhibit a fusiform morphology, with symmetrical circumferential enlargement involving all layers of the aortic wall. Less frequently, aneurysms have a saccular form, with aneurysmal degeneration affecting only part of the aortic circumference. The AAA wall usually becomes laminated with thrombus and its intraluminal diameter often appears relatively normal by angiography. Important histological features of aneurysms include chronic adventitial and medial inflammatory cell infiltration, elastin fragmentation and degeneration, and medial attenuation. Collagen (especially types I and III) in the media and adventitia provides tensile strength to the aortic wall. Collagen synthesis increases during the early stages of aneurysm formation, suggesting a repair process. 4 However, in later stages, collagen degradation exceeds its synthesis (accompanied by excessive degradation of other extracellular matrix macromolecules, notably elastin), ultimately favoring AAA rupture. Indeed, AAA exhibit increased local production of enzymes capable of degrading collagen and elastin extracellular matrix proteins. [5][6][7] In AAA, inflammatory cells (polymorphonuclear neutrophils, T cells, B cells, macrophages, mast c...

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Connective tissue proteinases and inhibitors in abdominal aortic aneurysms. Involvement of the vasa vasorum in the pathogenesis of aortic aneurysms.

Cited by 145 publications

References 44 publications

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

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

Angiotensin II Increases Urokinase-Type Plasminogen Activator Expression and Induces Aneurysm in the Abdominal Aorta of Apolipoprotein E-Deficient Mice

Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms

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