Differential expression of pro- and antiangiogenic factors in mouse strain-dependent hypoxia-induced retinal neovascularization

Chan, Candy King-Chi; Pham, Lucia N; Zhou, Jiehao; Spee, Christine; Ryan, Stephen J.; Hinton, David R.

doi:10.1038/labinvest.3700277

Cited by 66 publications

(47 citation statements)

References 41 publications

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“…12,41,42 How then do we explain the absence of Cd151 gene deletion effects in the oxygen-induced retinopathy (OIR) model? Retinal vascularization may be uniquely dependent on a preexisting astrocytic template.…”

Section: Discussionmentioning

confidence: 99%

Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro

Takeda

Kazarov

Butterfield

et al. 2006

Blood

155

235

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Tetraspanin protein CD151 is abundant on endothelial cells. To determine whether CD151 affects angiogenesis, Cd151-null mice were prepared. Cd151-null mice showed no vascular defects during normal development or during neonatal oxygeninduced retinopathy. However, Cd151-null mice showed impaired pathologic angiogenesis in other in vivo assays (Matrigel plug, corneal micropocket, tumor implantation) and in the ex vivo aortic ring assay. Cd151-null mouse lung endothelial cells (MLECs) showed normal adhesion and proliferation, but marked alterations in vitro, in assays relevant to angiogenesis (migration, spreading, invasion, Matrigel contraction, tube and cable formation, spheroid sprouting). Consistent with these functional impairments, and with the close, preferential association of CD151 with laminin-binding integrins, Cd151-null MLECs also showed selective signaling defects, particularly on laminin substrate. Adhesion-dependent activation of PKB/c-Akt, e-NOS, Rac, and Cdc42 was diminished, but Raf, ERK, p38 MAP kinase, FAK, and Src were unaltered. In Cd151-null MLECs, connections were disrupted between laminin-binding integrins and at least 5 other proteins. In conclusion, CD151 modulates molecular organization of laminin-binding integrins, thereby supporting secondary (ie, after cell adhesion) functions of endothelial cells, which are needed for some types of pathologic angiogenesis in vivo. Selective effects of CD151 on pathologic angiogenesis make it a potentially useful target for anticancer therapy. IntroductionAngiogenesis, the formation of new blood vessels from preexisting vasculature, is crucial for many physiologic and pathologic situations. [1][2][3] It involves coordinated endothelial cell proliferation, migration, and tube formation, with integrin-type adhesion receptors playing major roles. [4][5][6] Although vitronectin-, fibronectin-, and collagen-binding integrins have been most extensively studied, laminin-binding integrins (␣3␤1, ␣6␤1, ␣6␤4) are also involved. [7][8][9][10][11] For example, during the later stages of angiogenesis, ␣3␤1 and ␣6␤1 integrins may retard morphogenic and proliferative events, while promoting basement membrane assembly, pericyte association, and tube stabilization. 7 By contrast, ␣6␤4 may regulate the onset of pathologic angiogenesis in mature blood vessels. 12 CD151, a tetraspanin protein family member, 13 associates closely with laminin-binding integrins, thereby modulating ␣3␤1-, ␣6␤1-, and ␣6␤4-dependent neurite outgrowth, cell migration, cell morphology, and adhesion strengthening. Mutation of CD151 in humans yielded kidney and skin disorders, but no obvious impairments in blood vessel formation or function were noted. 14 Mice in which Cd151 was deleted were surprisingly normal, while showing only ex vivo deficiencies in platelet aggregation, keratinocyte migration, and T-cell proliferation. 15,16 Again, there were no obvious blood vessel deficiencies. CD151 is present on many cell types, including endothelial cells, where it may either promote 17 or inhibit 18...

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Section: Discussionmentioning

confidence: 99%

Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro

Takeda

Kazarov

Butterfield

et al. 2006

Blood

155

235

View full text Add to dashboard Cite

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“…In retinal endothelial cells, VEGF downregulated PEDF (Zhang et al, 2006b). There is also evidence that variability in oxygen-induced angiogenic responses in different strains of mice and rats is related to differences in VEGF and PEDF expression, VEGF lower and PEDF higher in the less angiogenic strains (Chan et al, 2005;Gao et al, 2001). In rats, part of the mechanism appears to be from a mediator upstream from the VEGF gene and promoter (Lu et al, 2007).…”

Section: Vegf To Pedf Ratiomentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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“…Many of these animal studies stem from genetically distinct mouse strains, such as the rd mouse, which possesses a mutation of rod-specific phosphodiesterase (Bowes et al, 1990;Jimenez et al, 1996). Other studies have focused attention on strain differences and metabolic consequences of light damage on retina during neonatal hyperoxia (Chan et al, 2005;Wu et al, 2006). However, much less is known about the environmental and metabolic contribution of tissue hypoxia to this process.…”

Section: Introductionmentioning

confidence: 99%

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

Yaung

Kannan

Wawrousek

et al. 2008

Experimental Eye Research

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This study evaluated the role of crystallins in retinal degeneration induced by chemical hypoxia. Wild type, αA-crystallin (−/−), and αB-crystallin (−/−) mice received intravitreal injection of 12 nmol (low dose), 33 nmol (intermediate dose) or 60 nmol (high dose) cobalt chloride (CoCl 2 ). Hematoxylin and eosin and TdT-mediated dUTP nick-end labeling (TUNEL) stains were performed after 24 hours, 96 hours, and 1 week post-injection, while immunofluorescent stains for αA-and αB-crystallin were performed 1 week post-injection. The in vitro effects of CoCl 2 on αB-crystallin expression in ARPE-19 cells were determined by real time RT-PCR, Western blot, and confocal microscopy and studies evaluating subcellular distribution of αB-crystallin in the mitochondria and cytosol were also performed. Histologic studies revealed progressive retinal degeneration with CoCl 2 injection in wild type mice. Retinas of CoCl 2 injected mice showed transient increased expression of HIF-1α which was maximal 24 hours after injection. Intermediate dose CoCl 2 injection was associated with increased retinal immunofluorescence for both αA-and αB-crystallin; however, after high dose injection, increased retinal degeneration was associated with decreased levels of crystallin expression. Injection of CoCl 2 at either intermediate or high dose in αA-crystallin (−/−) and αB-crystallin (−/−) mice resulted in much more severe retinal degeneration compared to wild type eyes. A decrease in ARPE-19 total and cytosolic αB-crystallin expression with increasing CoCl2 treatment and an increase in mitochondrial αB-crystallin were found. We conclude that lack of α-crystallins accentuates retinal degeneration in chemically-induced hypoxia in vivo.

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Differential expression of pro- and antiangiogenic factors in mouse strain-dependent hypoxia-induced retinal neovascularization

Cited by 66 publications

References 41 publications

Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro

Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro

Vascular endothelial growth factor in eye disease

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

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