Differential expression of angioregulatory factors in normal and CNV-derived human retinal pigment epithelium

Martin, Gottfried; Schlunck, Günther; Hansen, Lutz L.; Agostini, Hansjürgen

doi:10.1007/s00417-003-0838-y

Cited by 73 publications

(63 citation statements)

References 15 publications

(15 reference statements)

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“…Increased levels of repulsive guidance cues (including Sema3A) are released from choroidal neovascular retinal pigmented epithelium. 43 Guidance cues may therefore also contribute to diseases of the outer retina, such as age-related macular degeneration. Shortly after an ischemic stroke, 44 Sema3A is produced by injured cells 45,46 and localizes to regions immediately adjacent to the infarct.…”

Section: Discussionmentioning

confidence: 99%

Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A

Joyal

Sitaras

Binet

et al. 2011

Blood

161

199

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The failure of blood vessels to revascularize ischemic neural tissue represents a significant challenge for vascular biology. Examples include proliferative retinopathies (PRs) such as retinopathy of prematurity and proliferative diabetic retinopathy, which are the leading causes of blindness in children and working-age adults. PRs are characterized by initial microvascular degeneration, followed by a compensatory albeit pathologic hypervascularization mounted by the hypoxic retina attempting to reinstate metabolic equilibrium. Paradoxically, this secondary revascularization fails to grow into the most ischemic regions of the retina. Instead, the new vessels are misdirected toward the vitreous, suggesting that vasorepulsive forces operate in the avascular hypoxic retina. In the present study, we demonstrate that the neuronal guidance cue semaphorin 3A (Sema3A) IntroductionProliferative retinopathies (PRs) are traditionally perceived as disorders limited to the microvasculature because of the characteristic profuse and deregulated growth of retinal vessels. 1 The mechanisms by which neovessels grow toward the vitreous and fail to revascularize ischemic zones are thought to result from high concentrations of proangiogenic factors such as VEGF in the vitreous of PR patients. However, if such an explanation were sufficient, retinal glial cells (astrocytes and Müller cells) 2 and neurons 3 that produce vast amounts of growth factors under hypoxic conditions should retain vessels on the retinal surface and ensure revascularization of the retina proper. It is, therefore, compelling to hypothesize the presence of a vasorepulsive force originating from the significantly hypoxic avascular retina that repels neovessels away from the vaso-obliterated retina and grows toward the vitreous.Neurovascular cross-talk shapes vascular development but has received limited attention in the pathology setting. In PRs, evidence points to an early decline in the function of ischemic regions of the neural retina, as shown by multifocal electroretinogram (mfERG). 4,5 Throughout the vaso-obliterative phase of retinopathy, the local retinal environment is hostile to both vasculature and neurons. 6 After blood vessel degeneration, neurons are metabolically starved and undergo several adaptive cellular changes to counter the ischemic state of the tissue. 3,6 If adequate vascular supply is not reinstated in time to salvage deprived neurons, it is conceivable that these severely hypoxic cells may mount a repulsive front in an attempt to shunt metabolic resources away from the perishing ischemic tissue toward less affected regions of the retina. In the process, excessive production of VEGF 7 induces exaggerated neovascularization at the periphery of the ischemic and repulsive zones into the pre-retinal region (normally devoid of vasculature), because reestablishing a vascular network to neurons that are unsalvageable would be wasteful.Given their established role in influencing endothelial cell (EC) behavior, classic neuronal guidance cues may ...

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Section: Discussionmentioning

confidence: 99%

Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A

Joyal

Sitaras

Binet

et al. 2011

Blood

161

199

View full text Add to dashboard Cite

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“…However, VEGFR-1, but not the VEGFR-2 promoter, contains the hypoxia-inducible factor-1 ␣ binding sequence, a finding which could be directly involved in its hypoxia-induced upregulation [14] . The implication of VEGFR-1 in human pathology has recently been suggested by the observation that RPE cells within pathological specimens of choroidal neovascular membranes express only VEGFR-1 and not VEGFR-2 [15] . The expression of VEGFR-1 in human RPE cells may play a role in retinal diseases associated with VEGF production and could contribute to the pathogenesis of macular edema and to the growth of neovessels from the choriocapillaries through the RPE.…”

Section: Discussionmentioning

confidence: 99%

PlGF-1 and VEGFR-1 Pathway Regulation of the External Epithelial Hemato-Ocular Barrier

et al. 2008

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VEGF is considered as an important factor in the pathogenesis of macular edema. VEGF induces the rupture of the blood retinal barrier and may also influence the retinal pigment epithelial (RPE) outer retinal barrier. The aim of this work was to analyze the influence of the VEGF receptor pathways in the modulation of the RPE barrier breakdown in vitro and in vivo. The ARPE19 human junctions in culture are modulated by VEGF through VEGFR-1 but not through VEGFR-2. PlGF-1, that is a pure agonist of VEGFR-1, is produced in ARPE-19 cells under hypoxic conditions and mimics VEGF effects on the external retinal barrier as measured by TER and inulin flux. In vivo, the intravitreous injection of PlGF-1 induces a rupture of the external retinal barrier together with a retinal edema. This effect is reversible within 4 days. VEGF-E, that is a pure agonist of VEGFR-2, does not induce any acute effect on the RPE barrier. These results demonstrate that PlGF-1 can reproduce alterations of the RPE barrier occurring during diabetic retinopathy.

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“…Clinically, increased tumor HIF-1a is a marker of aggressive disease, associated with poor patient prognosis and treatment failure for a number of cancers, including breast, lung, ovarian, cervical, esophageal, and oropharyngeal cancers (17 -19). Activation of HIF-1 also occurs in relatively few normal tissues, for example, in skin during wound healing (20) and in diseases, such as age-related macular degeneration (21). Taken together, the experimental and clinical evidence suggest that inhibitors of HIF-1a may provide a new approach to cancer therapy (22,23).…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α

Koh

Spivak-Kroizman

Venturini

et al. 2008

Molecular Cancer Therapeutics

260

188

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We have reported previously that PX-478 (S-2-amino-3-[4 ¶-N,N,-bis(chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) has potent antitumor activity against a variety of human tumor xenografts associated with the levels of the hypoxia-inducible factor-1A (HIF-1A) within the tumor. We now report that PX-478 inhibits HIF-1A protein levels and transactivation in a variety of cancer cell lines. Hypoxia-induced vascular endothelial growth factor formation was inhibited by PX-478, whereas baseline levels of vascular endothelial growth factor in normoxia were unaffected. Studies of the mechanism of PX-478 action showed that HIF-1A inhibition occurs in both normoxia and hypoxia and does not require pVHL or p53. In addition, PX-478 decreases levels of HIF-1A mRNA and inhibits translation as determined by 35 S labeling experiments and reporter assays using the 5 ¶ untranslated region of HIF-1A. Moreover, to a lesser extent, PX-478 also inhibits HIF-1A deubiquitination resulting in increased levels of polyubiquitinated HIF-1A. The inhibitory effect of PX-478 on HIF-1A levels is primarily due to its inhibition of translation because HIF-1A translation continues in hypoxia when translation of most proteins is decreased. We conclude that PX-478 inhibits HIF-1A at multiple levels that together or individually may contribute to its antitumor activity against HIF-1A-expressing tumors. [Mol Cancer Ther 2008;7(1):90 -100]

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Differential expression of angioregulatory factors in normal and CNV-derived human retinal pigment epithelium

Cited by 73 publications

References 15 publications

Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A

Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A

PlGF-1 and VEGFR-1 Pathway Regulation of the External Epithelial Hemato-Ocular Barrier

Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α

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