Severe inhibition of choroidal neovascularization in mice with a combined deficiency of MMP-2 and MMP-9 genes

in Investigative Ophthalmology & Visual Science (2003, May), 44(Suppl. 2), 410

Role of plasminogen activator-plasmin system in tumor angiogenesis

in Cellular and Molecular Life Sciences : CMLS (2003), 60(3), 463-473

New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated ... [more ▼]

New blood formation or angiogenesis has become a key target in therapeutic strategies aimed at inhibiting tumor growth and other diseases associated with neovascularization. Angiogenesis is associated with important extracellular remodeling involving different proteolytic systems among which the plasminogen system plays an essential role. It belongs to the large serine proteinase family and can act directly or indirectly by activating matrix metalloproteinases or by liberating growth factors and cytokines sequestered within the extracellular matrix. Migration of endothelial cells is associated with significant upregulation of proteolysis and, conversely, immunoneutralization or chemical inhibition of the system reduces angiogenesis in vitro. On the other hand, genetically altered mice developed normally without overt vascular anomalies indicating the possibility of compensation by other proteases in vivo. Nevertheless, they have in some experimental settings revealed unanticipated roles for previously characterized proteinases or their inhibitors. In this review, the complex mechanisms of action of the serine proteases in pathological angiogenesis are summarized alongside possible therapeutic applications. [less ▲]

MMP-2 and MMP-9 synergize in promoting choroidal neovascularization

in FASEB Journal (2003), 17(15), 2290-2292

Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but ... [more ▼]

Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but their precise role and potential interactions remain unclear. To address the question of MMP-2 and MMP-9 functions, mice deficient in the expression of MMP-2 (MMP-2 KO), MMP-9 (MMP-9 KO), and both MMP-2 and MMP-9 (MMP-2,9 KO) with their corresponding wild-type mice (WT) underwent CNV induction by laser-induced rupture of the Bruch's membrane. Both the incidence and the severity of CNV were strongly attenuated in double deficient compared with single gene deficient mice or corresponding WT controls. The reduced neovascularization was accompanied by fibrinogen/fibrin accumulation. Furthermore, overexpression of the endogenous MMP inhibitors TIMP-1 or TIMP-2 (delivered by adenoviral vectors) in WT mice or daily injection of a synthetic and gelatinase selective MMP inhibitor (Ro 26-2853) significantly decreased the pathological reaction. These findings suggest that MMP-2 and MMP-9 may cooperate in the development of AMD and that their selective inhibition represents an alternative strategy for the treatment of choroidal neovascularization. [less ▲]

Matrix metalloproteinase-9 contributes to choroidal neovascularization

in American Journal of Pathology (2002), 161(4), 1247-1253

Age-related macular degeneration (AMD) is the primary cause of irreversible photoreceptors loss in adult patients and current therapies are limited. Increased levels of matrix metalloproteinases (MMPs ... [more ▼]

Age-related macular degeneration (AMD) is the primary cause of irreversible photoreceptors loss in adult patients and current therapies are limited. Increased levels of matrix metalloproteinases (MMPs) have been documented in neovascularization of severe ocular pathologies such as AMD and proliferative diabetic retinopathy. We report here that MMP-9 (gelatinase B) expression is induced and temporally regulated in the course of experimental choroidal neovascularization. We used transgenic mice expressing beta-galactosidase reporter gene under the dependence of MMP-9 promoter and RT-PCR analysis on choroidal neovascular structures microdissected from serial sections by laser pressure catapulting to show that MMP-9 expression is up-regulated concomitantly with the appearance of inflammatory cells in the subretinal lesion. In mice deficient in MMP-9 expression the development of choroidal neovascularization induced by laser photocoagulation still occurred, but at a reduced level. [less ▲]

Influence of Plasminogen Activator Inhibitor Type 1 on Choroidal Neovascularization

in FASEB Journal (2001), 15(6), 1021-7

High levels of the plasminogen activators, but also their inhibitor, plasminogen activator inhibitor 1 (PAI-1), have been documented in neovascularization of severe ocular pathologies such as diabetic ... [more ▼]

High levels of the plasminogen activators, but also their inhibitor, plasminogen activator inhibitor 1 (PAI-1), have been documented in neovascularization of severe ocular pathologies such as diabetic retinopathy or age-related macular degeneration (AMD). AMD is the primary cause of irreversible photoreceptors loss, and current therapies are limited. PAI-1 has recently been shown to be essential for tumoral angiogenesis. We report here that deficient PAI-1 expression in mice prevented the development of subretinal choroidal angiogenesis induced by laser photocoagulation. When systemic and local PAI-1 expression was achieved by intravenous injection of a replication-defective adenoviral vector expressing human PAI-1 cDNA, the wild-type pattern of choroidal angiogenesis was restored. These observations demonstrate the proangiogenic activity of PAI-1 not only in tumoral models, but also in choroidal experimental neovascularization sharing similarities with human AMD. They identify therefore PAI-1 as a potential target for therapeutic ocular anti-angiogenic strategies. [less ▲]

Regulation of cancer invasion and vascularization by plasminogen activator inhibitor-1

in Fibrinolysis and Proteolysis (1999), 13(6), 220-225

Acquisition of invasive/metastatic potential through protease expression is a key event in tumor progression. The proteolytic enzyme plasmin is generated from the precursor plasminogen by the action of ... [more ▼]

Acquisition of invasive/metastatic potential through protease expression is a key event in tumor progression. The proteolytic enzyme plasmin is generated from the precursor plasminogen by the action of urokinase-type plasminogen activator (urokinase, uPA) or tissue-type plasminogen activator (tPA). Plasminogen activator inhibitor-1 or PAI-1 is the main inhibitor of uPA and tPA. High levels of components of this proteolytic system, including uPA and its cell surface receptor (uPAR), have been correlated with a poor prognosis for different cancers. It was therefore anticipated that PAI-1 expression would be associated with favorable outcome. Paradoxically, high rather than low PAI-1 levels predict poor survival of patients suffering from a variety of cancers. Recent observations indicate a much more complex role of PAI-1 in tumor progression and angiogenesis than initially expected. The exact mechanisms of this multifunctional molecule remain puzzling. [less ▲]

Ultrastructural Modifications in Cultured Fetal Quail Hepatocytes Exposed to Pesticides and Pcbs

in Ecotoxicology & Environmental Safety (1996), 34(2), 145-55

There is increasing interest in cultured hepatocytes as a tool for solving toxicological and pharmacological problems while reducing laboratory animal experimentation. In the present study, fetal ... [more ▼]

There is increasing interest in cultured hepatocytes as a tool for solving toxicological and pharmacological problems while reducing laboratory animal experimentation. In the present study, fetal hepatocytes from the Japanese quail (Coturnix coturnix japonica) were used as an in vitro alternative model for evaluating the effects of PCBs and various pesticide-type chemicals on cell ultrastructure. Major alterations were demonstrated. The most striking effects of toxicants were an increase in the number of cisternae of the rough endoplasmic reticulum (RER), various alterations of mitochondrial morphology, a decreased glycogen content, vacuolization of the cytoplasm, and the appearance of concentric membrane arrays (CMA's), also called myelin-like figures. Other changes were sometimes observed, such as altered cell junctions, an increased lipid content, deformations of the nuclei, or the appearance of crystalline structures. These ultrastructural modifications seem to be dose-dependent. The present in vitro findings are validated by similar observations previously made in vivo on Japanese quail. They confirm the effectiveness of this technique as a biomonitoring tool for the evaluation of environmental quality. Yet the multiplicity of possible toxic effects, even for xenobiotics of a same category, makes it necessary to screen additional indicators of toxicity, such as the detoxifying activity of monooxygenases. [less ▲]