Metalloproteases and intracranial vascular lesions

Gaetani, Paolo; Baena, Riccardo Rodriguez y; Tartara, Fulvio; Messina, Alberto Luca; Tancioni, Flavio; Schiavo, Roberta; Grazioli, Vittorio

doi:10.1080/01616412.1999.11740948

Cited by 45 publications

(29 citation statements)

References 33 publications

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“…Some deformation of femoral arteries in MMP-9-knockout mice was seen during surgical procedures. It is also possible that changes in collagenase or elastase in the brain tissues including major arteries or microvessels contribute to this effect (Ducharme et al, 2000;Gaetani et al, 1999). Enhanced expression of collagenases (MMP-1, MMP-8, MMP-13, and MMP-18) and elastases in the MMP-9-deficient mice might promote a more severe bleeding after external collagenase-injection, a possibility which requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

Tang

Zhou

et al. 2004

J Cereb Blood Flow Metab

160

141

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Summary:Matrix metalloproteinase-9 (MMP-9) participates in the disregulation of blood-brain barrier during hemorrhagic transformation, and exacerbates brain injury after cerebral ischemia. However, the consequences of long-term inhibition or deficiency of MMP-9 activity (which might affect normal collagen or matrix homeostasis) remains to be determined. The authors investigated how MMP-9 gene deficiency enhances hemorrhage and increases mortality and neurologic deficits in a collagenase-induced intracerebral hemorrhage (ICH) model in MMP-9-knockout mice. MMP-9-knockout and corresponding wild-type mice at 20 to 35 weeks were used to model an aged population (because advanced age is a significant risk factor in human ICH). Collagenase VII-S (0.5 L, 0.075 U) was injected into the right basal ganglia in mice and mortality, neurologic deficits, brain edema, and hemorrhage size measured. In addition, MMP-9 activity, brain collagen content, blood coagulation, cerebral arterial structure, and expressions of several MMPs were examined. Increased hemorrhage and brain edema that correlated with higher mortality and neurologic deficits were found in MMP-9-knockout mice. No apparent structural changes were observed in cerebral arteries, even though brain collagen content was reduced in MMP-9-knockout mice. MMP-9-knockout mice did exhibit an enhanced expression of MMP-2 and MMP-3 in response to ICH. The results indicate that a deficiency of MMP-9 gene in mutant mice increases collagenase-induced hemorrhage and the resulting brain injury. The intriguing relationship between MMP-9 deficiency and collagenase-induced ICH may reflect the reduction in collagen content and an enhanced expression of MMP-2 and MMP-3. Key Words: MMP-9-Intracerebral hemorrhage-Collagenase-Edema-Blood-brain barrier-Coagulation.Spontaneous intracerebral hemorrhage (ICH) is one of the most serious stroke events, and results in high mortality and morbidity in patients (Bernardini and DeShaies, 2001;Panagos et al., 2002;Woo and Broderick, 2002). Mortality in ICH is often as high as 50% within the first month after ICH, with 50% of these deaths occurring within 48 hours (Broderick, 1993). The mechanisms of ICH-induced early brain injury (e.g. brain edema) have been investigated (Altumbabic et al., 1998;Del Bigio et al., 1999;Xi et al., 2002); however, the complete etiology of early brain injury in ICH is incompletely understood.Matrix metalloproteinases (MMPs) are involved in the pathogenesis of cerebral vascular disorders, particularly the formation and rupture of aneurysms. For example, pro-MMP-2 has been implicated as a significant component within arterial walls of intracerebral aneurysms that leads to subarachnoid hemorrhage (Todor et al., 1998). Other studies also support elevated MMP (elastase and collagenase) activity in ruptured vessels in subarachnoid hemorrhage but not in unruptured aneurysms (Gaetani et al., 1999). MMPs are also involved in the hemorrhagic transformation after cerebral ischemia, especially after thrombolysis (Hosomi et al., 2001;M...

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Section: Discussionmentioning

confidence: 99%

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

Tang

Zhou

et al. 2004

J Cereb Blood Flow Metab

160

141

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“…We observed decreased Ang1 protein levels despite normal Ang1 mRNA levels, which may suggest increased proteolytic activity in BAVMs. 13 Stimuli such as shear stress or ischemia may also affect the expression of Ang and Tie2. However, BAVM vessels are exposed to high rates of fully oxygenated blood flow 2 and are therefore unlikely to be ischemic.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Balance in the Angiopoietin-Tie2 System in Human Brain Arteriovenous Malformations

Hashimoto

Lam²,

Boudreau³

et al. 2001

Circulation Research

104

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Brain arteriovenous malformations (BAVMs) are congenital vascular lesions that often present as cerebral hemorrhage in young adults. The variable nature of the clinical course, especially with respect to spontaneous hemorrhage, recurrence, growth, and regression, suggests that BAVMs are lesions with active angiogenesis and vascular remodeling. We examined mRNA and protein expression of angiopoietin 1 (Ang1) and Ang2 by semiquantitative reverse transcriptase-polymerase chain reaction, in situ hybridization, and Western blot in BAVMs and control brains obtained from temporal lobectomy for medically intractable seizures. Although Ang1 mRNA levels were similar in BAVMs and controls, Ang1 protein levels were 30% lower in BAVMs than in controls. Ang2 mRNA levels were 40% higher and Ang2 protein levels were 8-fold higher in BAVMs than in controls. In situ hybridization showed that the Ang2 mRNA was localized to the perivascular area in BAVMs. This abnormal balance in the Ang-Tie2 system may, in part, explain the aberrant vascular phenotype in BAVMs.

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“…45 In humans, the levels of elastase and the ratios of elastase versus ␣ 1 -antitrypsin are higher in patients with ruptured or unruptured intracranial aneurysms than in controls. 46,47 In addition, compared with unruptured aneurysms, ruptured aneurysms have higher elastase activities in the artery wall, 46 whereas serum ␣ 1 -antitrypsin activity, which is influenced by smoking, is lower in patients with ruptured aneurysms than in those with unruptured aneurysms. 48 Taken together, these studies suggest that elastase/ ␣ 1 -antitrypsin imbalance in cigarette smokers may also contribute to aneurysm formation and/or rupture.…”

Section: Zhang Et Al Matrix Metalloproteinase Genes and Subarachnoid mentioning

confidence: 99%

Polymorphisms in Matrix Metalloproteinase-1, -3, -9, and -12 Genes in Relation to Subarachnoid Hemorrhage

Zhang

Dhillon

Geary

et al. 2001

Stroke

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Background and Purpose-Intracranial aneurysm, which underlies the vast majority of subarachnoid hemorrhage incidences, has a multifactorial etiology, and the importance of genetic factors is increasingly recognized. Development and rupture of intracranial aneurysms involve degradation and remodeling of the vascular wall matrix in which the matrix metalloproteinases (MMPs) play an important role. The possible impact of MMP gene polymorphisms on susceptibility to intracranial aneurysms is still controversial, with conflicting data from different reported studies. Methods-In this study we analyzed 5 different functional promoter polymorphisms in the MMP-1, MMP-3, MMP-9, and MMP-12 genes in a sample of 92 patients with aneurysmal subarachnoid hemorrhage and 158 healthy control subjects, all from southern England. Results-No significant difference was detected between the patient and control groups in genotype distribution of any of the polymorphisms studied. Conclusions-The

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Metalloproteases and intracranial vascular lesions

Cited by 45 publications

References 33 publications

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

MMP-9 Deficiency Enhances Collagenase-Induced Intracerebral Hemorrhage and Brain Injury in Mutant Mice

Abnormal Balance in the Angiopoietin-Tie2 System in Human Brain Arteriovenous Malformations

Polymorphisms in Matrix Metalloproteinase-1, -3, -9, and -12 Genes in Relation to Subarachnoid Hemorrhage

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