The elastase infusion model of experimental aortic aneurysms: Synchrony of induction of endogenous proteinases with matrix destruction and inflammatory cell response

Halpern, Vivienne J.; Nackman, Gary B.; Gandhi, Raju H.; Irizarry, Evelyn; Scholes, John V.; Ramey, William G.; Tilson, M. David

doi:10.1016/0741-5214(94)90175-9

Cited by 122 publications

(88 citation statements)

References 7 publications

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“…4,7 IEL disruption is necessary in aneurysm initiation to allow the vessel wall to expand outward. 2,4 Whereas IEL disruption in abdominal aortic aneurysms is due to matrix metalloproteinases, mostly secreted by infiltrating macrophages that precede aneurysm formation, 21 in cerebral aneurysms there is no evidence that inflammatory cells are present during initiation, 4 and they were not found in our created bifurcations. We speculate that in the acceleration region, the combination of a high WSS and a high WSSG induced matrix metalloproteinase production by ECs and SMCs.…”

Section: Aneurysm-type Remodeling In the Acceleration Regionmentioning

confidence: 88%

Complex Hemodynamics at the Apex of an Arterial Bifurcation Induces Vascular Remodeling Resembling Cerebral Aneurysm Initiation

Meng

Wang

Hoi

et al. 2007

Stroke

518

476

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Background and Purpose-Arterial bifurcation apices are common sites for cerebral aneurysms, raising the possibility that the unique hemodynamic conditions associated with flow dividers predispose the apical vessel wall to aneurysm formation. This study sought to identify the specific hemodynamic insults that lead to maladaptive vascular remodeling associated with aneurysm development and to identify early remodeling events at the tissue and cellular levels. Methods-We surgically created new branch points in the carotid vasculature of 6 female adult dogs. In vivo angiographic imaging and computational fluid dynamics simulations revealed the detailed hemodynamic microenvironment for each bifurcation, which were then spatially correlated with histologic features showing specific tissue responses. Results-We observed 2 distinct patterns of vessel wall remodeling: (1) hyperplasia that formed an intimal pad at the bifurcation apex and (2) destructive remodeling in the adjacent region of flow acceleration that resembled the initiation of an intracranial aneurysm, characterized by disruption of the internal elastic lamina, loss of medial smooth muscle cells, reduced proliferation of smooth muscle cells, and loss of fibronectin. Conclusions-Strong localization of aneurysm-type remodeling to the region of accelerating flow suggests that a combination of high wall shear stress and a high gradient in wall shear stress represents a "dangerous" hemodynamic condition that predisposes the apical vessel wall to aneurysm formation.

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Section: Aneurysm-type Remodeling In the Acceleration Regionmentioning

confidence: 88%

Complex Hemodynamics at the Apex of an Arterial Bifurcation Induces Vascular Remodeling Resembling Cerebral Aneurysm Initiation

Meng

Wang

Hoi

et al. 2007

Stroke

518

476

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“…Many of these studies have involved an elastase-induced rat model of AAAs, in which a chronic aortic wall inflammatory response is associated with progressive elastic fiber degradation and aneurysmal dilatation (13,14). Elastase-induced inflammation is accompanied by increased aortic wall production of MMPs (15), and treatment with antiinflammatory agents or MMP antagonists leads to preservation of medial elastin and a reduction in aneurysm development (16)(17)(18)(19). These and other investigations have led to a conceptual model of aneurysm disease that emphasizes the role of inflammatory cellderived metalloproteinases, acting in a cascade, to mediate the degradation of aortic wall elastic fibers.…”

mentioning

confidence: 99%

Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms

et al. 2000

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“…6,7 The mechanism of aneurysm formation in animal models of AAA has often been related to an elastase-induced inflammatory response, which leads to destruction of the extracellular matrix proteins. 8,9 Although the role of elastase-induced degradation of the extracellular matrix component of the vascular wall during AAA formation has been extensively studied, 8,9 little is known regarding the effects of elastase on other vascular cell types, particularly on the mechanisms of aortic smooth muscle contraction.…”

mentioning

confidence: 99%

Elastase-Induced Suppression of Endothelin-Mediated Ca ²⁺ Entry Mechanisms of Vascular Contraction

Chew¹,

Orshal

Khalil

2003

Hypertension

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Abstract-Abdominal aortic aneurysm (AAA) is associated with increased endothelin (ET-1), both systemically and locally in the aorta. Also, elastase activity is increased in human AAA, and elastase perfusion of the aorta induces aneurysm formation in animal models of AAA. However, whether elastase directly affects the ET-1-induced mechanisms of aortic smooth muscle contraction is unclear. Isometric contraction and 45 Ca 2ϩ influx were measured in aortic strips isolated from male Sprague-Dawley rats and treated with elastase (5 U/mL). To avoid degradation of the extracellular matrix proteins by elastase, experiments were performed in the presence of elastin (10 mg/mL). In normal Krebs solution (2.5 mmol/L Ca 2ϩ ), ET-1 (10 Ϫ7 mol/L) caused contraction of aortic strips that was inhibited by elastase (5 U/mL). The elastase-induced inhibition of ET-1 contraction was slow in onset (4.6Ϯ0.4 minutes), time-dependent, complete in 34Ϯ3 minutes, and reversible. In Ca 2ϩ -free Krebs solution, caffeine (25 mmol/L) caused a small contraction that was not inhibited by elastase, suggesting that elastase does not inhibit Ca 2ϩ release from the intracellular stores. Membrane depolarization by 96 mmol/L KCl, which stimulates Ca 2ϩ entry from the extracellular space, caused a contraction that was inhibited by elastase in a concentration-dependent, time-dependent, and reversible fashion. The reversible inhibitory effects of elastase, particularly in the presence of elastin, suggest that they are not due to dissolution of the extracellular matrix or smooth muscle contractile proteins. Elastase also inhibited ET-1 and KCl-induced

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The elastase infusion model of experimental aortic aneurysms: Synchrony of induction of endogenous proteinases with matrix destruction and inflammatory cell response

Abstract: The results suggest that the latency in AAA formation in this model corresponds with a complex sequence of biochemical and cellular events. The model provides an "early window" into these interesting early phases leading to aneurysm formation.

Cited by 122 publications

References 7 publications

Complex Hemodynamics at the Apex of an Arterial Bifurcation Induces Vascular Remodeling Resembling Cerebral Aneurysm Initiation

Complex Hemodynamics at the Apex of an Arterial Bifurcation Induces Vascular Remodeling Resembling Cerebral Aneurysm Initiation

Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms

Elastase-Induced Suppression of Endothelin-Mediated Ca ²⁺ Entry Mechanisms of Vascular Contraction

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The elastase infusion model of experimental aortic aneurysms: Synchrony of induction of endogenous proteinases with matrix destruction and inflammatory cell response

Abstract: The results suggest that the latency in AAA formation in this model corresponds with a complex sequence of biochemical and cellular events. The model provides an "early window" into these interesting early phases leading to aneurysm formation.

Cited by 122 publications

References 7 publications

Complex Hemodynamics at the Apex of an Arterial Bifurcation Induces Vascular Remodeling Resembling Cerebral Aneurysm Initiation

Complex Hemodynamics at the Apex of an Arterial Bifurcation Induces Vascular Remodeling Resembling Cerebral Aneurysm Initiation

Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms

Elastase-Induced Suppression of Endothelin-Mediated Ca 2+ Entry Mechanisms of Vascular Contraction

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Elastase-Induced Suppression of Endothelin-Mediated Ca ²⁺ Entry Mechanisms of Vascular Contraction