Prolactins Are Natural Inhibitors of Angiogenesis in the Retina

Aranda, Jorge; Rivera, José Carlos; Jeziorski, Michael C.; Riesgo-Escovar, Juan R.; Nava, Gabriel Miranda; López-Barrera, Fernándo; Quiroz‐Mercado, Hugo; Berger, Peter; Escalera, Gonzálo Martínez de la; Clapp, Carmen

doi:10.1167/iovs.05-0173

Cited by 72 publications

(86 citation statements)

References 41 publications

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“…28 Vasoinhibins comprise a family of peptides that are generated by the specific proteolytic cleavage of prolactin and they exert potent antiangiogenic and anti-vasopermeability effects. 29 Vasoinhibins are found in the retina, 7 and their systemic concentration is reduced in patients with DR. 30 Figure 5 The AAV2 vasoinhibin and AAV2 sFlt-1 vectors fail to reduce diabetes-induced blood-retinal barrier pathology when injected prior to inducing diabetes. Pre-diabetes design diagram: vehicle (Veh), or AAV2 Vi, or AAV2 sFlt-1 vectors were injected intravitreally in non-diabetic rats (ND) or into rats (D) 4 weeks before treatment with STZ, and the retinal permeation of Evans blue-stained albumin was evaluated 8 weeks after vector administration.…”

Section: Discussionmentioning

confidence: 99%

“…7 Four weeks after vector administration, some of the animals were anesthetized as above, and the BRBB was examined by the Evans blue method; other animals were subjected to fluorescein angiography, or to electroretinogram (ERG) examination and killed by decapitation to analyze retinal thickness. In addition, other rats were exposed to a CO 2 -saturated inhalation chamber and killed by decapitation; their retinas were analyzed by quantitative PCR (qPCR) or flat-mounted for confocal microscopy evaluation.…”

Section: Animalsmentioning

confidence: 99%

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Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Díaz‐Lezama

Adán‐Castro

et al. 2016

Laboratory Investigation

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Adeno-associated virus (AAV) vector-mediated delivery of inhibitors of blood-retinal barrier breakdown (BRBB) offers promise for the treatment of diabetic macular edema. Here, we demonstrated a reversal of blood-retinal barrier pathology mediated by AAV type 2 (AAV2) vectors encoding vasoinhibin or soluble VEGF receptor 1 (sFlt-1) when administered intravitreally to diabetic rats. Efficacy and safety of the AAV2 vasoinhibin vector were tested by monitoring its effect on diabetes-induced changes in the retinal vascular bed and thickness, and in the electroretinogram (ERG). Also, the transduction of AAV2 vectors and expression of AAV2 receptors and co-receptors were compared between the diabetic and the non-diabetic rat retinas. AAV2 vasoinhibin or AAV2 sFlt-1 vectors were injected intravitreally before or after enhanced BRBB due to diabetes induced by streptozotocin. The BRBB was examined by the Evans blue method, the vascular bed by fluorescein angiography, expression of the AAV2 EGFP reporter vector by confocal microscopy, and the AAV2 genome, expression of transgenes, receptors, and co-receptors by quantitative PCR. AAV2 vasoinhibin and sFlt-1 vectors inhibited the diabetes-mediated increase in BRBB when injected after, but not before, diabetes was induced. The AAV2 vasoinhibin vector decreased retinal microvascular abnormalities and the diabetes-induced reduction of the B-wave of the ERG, but it had no effect in non-diabetic controls. Also, retinal thickness was not altered by diabetes or by the AAV2 vasoinhibin vector. The AAV2 genome, vasoinhibin and sFlt-1 transgenes, and EGFP levels were higher in the retinas from diabetic rats and were associated with an elevated expression of AAV2 receptors (syndecan, glypican, and perlecan) and co-receptors (fibroblast growth factor receptor 1, αvβ5 integrin, and hepatocyte growth factor receptor). We conclude that retinal transduction and efficacy of AAV2 vectors are enhanced in diabetes, possibly due to their elevated cell entry. AAV2 vectors encoding vasoinhibin and sFlt-1 may be desirable gene therapeutics to target diabetic retinopathy and macular edema.

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Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Díaz‐Lezama

Adán‐Castro

et al. 2016

Laboratory Investigation

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“…There has been an ongoing effort during the last decades to identify these factors and investigate their relevance in pathophysiological conditions (18). PRL-V has been identified as a natural inhibitor of angiogenesis in the retina (12), by inhibiting VEGF-mediated retinal vasopermeability (13) and antagonizing proangiogenic effects of VEGF (8). Angiogenesis and increased vasopermeability of retinal vessels are pathologic processes occurring in diabetic retinopathy.…”

Section: Discussionmentioning

confidence: 99%

Investigation of prolactin-related vasoinhibin in sera from patients with diabetic retinopathy

Triebel

Huefner²,

Ramadori³

2009

European Journal of Endocrinology

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ObjectiveIn vitro experiments and in vivo studies on rodents demonstrate that N-terminal 14, 15, 16, 17, and 18 kDa fragments prolactin-related vasoinhibin (PRL-V) of human PRL are natural inhibitors of neovascularization in the retina and elsewhere. These N-terminal PRL fragments belong to a family of peptides named vasoinhibins, which act as endogenous regulators of angiogenesis and vascular function. These observations led to the hypothesis that PRL-V could play a role in the pathophysiology of diabetic retinopathy in humans. The purpose of this study was to investigate whether patients with diabetes mellitus and diabetic retinopathy have aberrant concentrations of PRL-V in the circulating blood.Research designWe performed a case–control study and developed a new technique to semi-quantitatively determine PRL-V in serum samples from 48 male subjects. The case group consisted of 21 patients with diabetes mellitus and proliferative or non-proliferative diabetic retinopathy. The control group consisted of 27 healthy subjects with no history of diabetes mellitus.MethodsFor the detection of PRL-V, we developed a new analytical method, consisting of immunologic and laser-induced fluorescence techniques.ResultsThe case group had significantly lower PRL-V serum concentrations than the control group (P=0.041). There was no significant difference between patients with proliferative and those with non-proliferative diabetic retinopathy.ConclusionWe conclude that given the antiangiogenic and antivasopermeability actions of PRL-V, the decreased serum levels of PRL-V in patients with diabetes mellitus could contribute to the development and progression of diabetic retinopathy.

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“…No signal was detected in the negative control without reverse transcriptase. The presence of PRL proteins was investigated by western blotting, using INN-368 or INN-1 monoclonal antibodies that selectively recognize the Cterminal or the N-terminal end of PRL, respectively (Aranda et al, 2005). Selectivity was confirmed by comparing antibody binding to a mixture of purified rat standards of 23K-PRL, Nterminal 16K-PRL (residues 1-145), and C-terminal 6 kDa PRL (6K-PRL, residues 149-198) (Fig.…”

Section: Journal Of Cell Science 119 (9)mentioning

confidence: 99%

Matrix metalloproteases from chondrocytes generate an antiangiogenic 16 kDa prolactin

Macotela

Aguilar

Guzmán-Morales

et al. 2006

Journal of Cell Science

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The 16 kDa N-terminal fragment of prolactin (16K-prolactin) is a potent antiangiogenic factor. Here, we demonstrate that matrix metalloproteases (MMPs) produced and secreted by chondrocytes generate biologically functional 16K-prolactin from full-length prolactin. When incubated with human prolactin at neutral pH, chondrocyte extracts and conditioned medium, as well as chondrocytes in culture, cleaved the Ser155-Leu156 peptide bond in prolactin, yielding - upon reduction of intramolecular disulfide bonds - a 16 kDa N-terminal fragment. This 16K-prolactin inhibited basic fibroblast growth factor (FGF)-induced endothelial cell proliferation in vitro. The Ser155-Leu156 site is highly conserved, and both human and rat prolactin were cleaved at this site by chondrocytes from either species. Conversion of prolactin to 16K-prolactin by chondrocyte lysates was completely abolished by the MMP inhibitors EDTA, GM6001 or 1,10-phenanthroline. Purified MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13 cleaved human prolactin at Gln157, one residue downstream from the chondrocyte protease cleavage site, with the following relative potency: MMP-8>MMP-13 >MMP-3>MMP-1=MMP-2>MMP-9. Finally, chondrocytes expressed prolactin mRNA (as revealed by RT-PCR) and they contained and released antiangiogenic N-terminal 16 kDa prolactin (detected by western blot and endothelial cell proliferation). These results suggest that several matrix metalloproteases in cartilage generate antiangiogenic 16K-prolactin from systemically derived or locally produced prolactin.

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Prolactins Are Natural Inhibitors of Angiogenesis in the Retina

Abstract: These results demonstrate that PRL is synthesized and cleaved to antiangiogenic 16K-PRL by retinal tissue and that these molecules play a key role in preventing angiogenesis in the healthy retina.

Cited by 72 publications

References 41 publications

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Investigation of prolactin-related vasoinhibin in sera from patients with diabetic retinopathy

Matrix metalloproteases from chondrocytes generate an antiangiogenic 16 kDa prolactin

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