Inhibition of pathologic retinal neovascularization by  -defensins

Abstract

Proliferative retinopathies, such as those complicating prematurity and diabetes, are major causes of blindness. A prominent feature of these retinopathies is excessive neovascularization, which is orchestrated by the hypoxia-induced vascular endothelial growth factor (VEGF) stimulating endothelial cells and the integrin-mediated adhesive interactions of endothelial cells with extracellular matrix components such as fibronectin (FN). Recently, we demonstrated that ␣-defensins interfere with ␣5␤1-FN interactions and dependent endothelial cell functions. Here, ␣-defensins were studied in hypoxia-induced proliferative retinopathy. In vitro, ␣-defensins specifically inhibited ␣5␤1-integrin-dependent migration of bovine retinal endothelial cells (BRECs) to FN, attenuated the VEGF-stimulated increase in endothelial permeability, and blocked BREC proliferation and capillary sprout formation in 3-dimensional fibrinmatrices. An up-regulation of ␤1-integrin and FN was observed in the retinal vessels in the mouse model of hypoxiainduced retinal angiogenesis. Systemic and local administration of ␣-defensins reduced retinal neovascularization by 45% and 60%, respectively, and this effect was comparable to the inhibitory effect of ␣5␤1-blocking antibody. ␣-Defensins were detected in human diabetic retinas associated with normal retinal vessels but were absent from proliferative lesions. Together, these data show that ␣-defensins inhibit pathologic retinal neovascularization in vivo and may provide a clinically efficient strategy against proliferative retinopathies. IntroductionRetinopathy of prematurity and proliferative diabetic retinopathy are the major causes of neonatal and adult blindness, respectively. 1 Pathologic retinal neovascularization is ectopic-that is, the new vessels invade the vitreous cavity, resulting in vision-threatening complications, such as vitreous hemorrhage and retinal detachment. During proliferative retinopathy, neovascularization is regulated by several growth factors, especially the hypoxia-induced vascular endothelial growth factor (VEGF) that regulates endothelial cell proliferation, migration, and permeability and by the adhesive contacts of endothelial cells with the extracellular matrix. [2][3][4] Proteins of the extracellular matrix, such as fibronectin (FN), vitronectin (VN), and fibrinogen (FBG), are deposited into an adhesive fibrillar network and control endothelial growth, differentiation, and migration by transmitting signals to the cells through specific integrins. 5-8 Accordingly, we and others 9,10 have previously shown that interference with integrin-extracellular matrix interactions and blockade of VEGF are effective in inhibiting retinal neovascularization in a mouse model of hypoxia-induced retinal angiogenesis.Emerging evidence indicates that inflammatory cells may regulate endothelial cell functions related to angiogenesis in proliferative retinopathies. In retinopathy of prematurity and in diabetic retinopathy, leukocyte adhesion to retinal structures may lead to blood-ret...

Human α-defensin-1 inhibits growth of human lung adenocarcinoma xenograft in nude mice

“…Moreover, HNP can form a ternary complex with fibronectin and a 5 h 1 integrin and further affect endothelial cell adhesion, migration, and proliferation (10). HNP have also been shown to attenuate endothelial permeability and proliferation stimulated by the vascular endothelial growth factor and fibroblast growth factor in vivo (9). In this study, a lower density of vessels was found in tumor tissues treated with pSec-HNP1 by anti-CD31 staining, which indicates that tumor angiogenesis is effectively inhibited.…”

“…Previous studies have shown that HNP1 has an effect on angiogenesis via affecting endothelial cell in pathologic retinal neovascularization and inflammation (9,10). To investigate its role in tumor angiogenesis, we did immunohistochemical staining with anti-CD31.…”

“…In addition, HNP can regulate angiogenesis by affecting endothelial cell adhesion and migration in a fibronectindependent manner as well as endothelial cell proliferation (9,10). Inhibition of angiogenesis through HNP1 would increase its antitumor effect, because antiangiogenesis has proven an effective strategy for treatment of cancer patients (11).…”

Intratumoral expression of mature human neutrophil peptide-1 potentiates the therapeutic effect of doxorubicin in a mouse 4T1 breast cancer model

“…Inhibition of VEGF or its kinase receptors (VEGFRs) can cause normalization of tumor vasculature (20,21). It is reported that HNP1 could impair VEGF-mediated angiogenesis (19,28). In the present study, to avoid the influence of the plasmid vector on angiogenesis, a mature HNP1 peptide was injected intratumorally in the 4T1 tumors and normalized microvessels of orderly formed EC monolayer were observed after treatment.…”

“…Inhibition of VEGF or its kinase receptors (VEGFRs) could result in tumor vasculature normalization (20,21). It has been reported that HNP1 impairs VEGF-mediated angiogenesis (19,28). To detect the influence of HNP1 on tumor microvessels, a commercial HNP1 peptide was injected intratumorally, and ultrastructural changes were observed by transmission electron microscopy.…”