Vasoinhibins prevent retinal vasopermeability associated with diabetic retinopathy in rats via protein phosphatase 2A–dependent eNOS inactivation

García, Celina; Aranda, Jorge; Arnold, Edith; Thebault, Stéphanie; Macotela, Yazmín; López‐Casillas, Fernando; Mendoza, Valentín; Quiroz‐Mercado, Hugo; Hernández‐Montiel, Hebert Luis; Lin, Sue Hwa; Escalera, Gonzálo Martínez de la; Clapp, Carmen

doi:10.1172/jci34508

Cited by 60 publications

(113 citation statements)

References 68 publications

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“…32,33 The effects of vasoinhibins 3,32,33 and sFlt-1 34,35 against BRBB have been well-documented using Evans blue and a variety of other in vivo and in vitro techniques that have revealed signaling mechanisms mediating their action. For example, VEGF antagonists and vasoinhibins block calcium influx through transient receptor potential channels; they also inhibit the activation of phospholipase C gamma and phosphatidylinositol-3-kinase-Akt mechanisms, thereby leading to downstream blockage of eNOS activation and the reinforcement of junctional proteins linked to the actin cytoskeleton.…”

Section: Aav2 Vectors Reverse Diabetic Retinal Alterations N Díaz-lezmentioning

confidence: 99%

“…For example, VEGF antagonists and vasoinhibins block calcium influx through transient receptor potential channels; they also inhibit the activation of phospholipase C gamma and phosphatidylinositol-3-kinase-Akt mechanisms, thereby leading to downstream blockage of eNOS activation and the reinforcement of junctional proteins linked to the actin cytoskeleton. 32,33,[36][37][38] AAV-mediated gene transfer of sFlt-1 successfully reduces BRBB when the vector is delivered before diabetes manifests in the spontaneously diabetic Torii rat. 34 AAV2 vectors encoding sFlt-1 or vasoinhibin also reduce BRBB in rats when injected before inducing diabetes with STZ.…”

Section: Aav2 Vectors Reverse Diabetic Retinal Alterations N Díaz-lezmentioning

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: Aav2 Vectors Reverse Diabetic Retinal Alterations N Díaz-lezmentioning

confidence: 99%

Section: Aav2 Vectors Reverse Diabetic Retinal Alterations N Díaz-lezmentioning

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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“…The production of endothelial derived NO results from the calcium-calmodulin activation of eNOS via phosphatidylinositol 3-kinase, followed by the phosphorylation of eNOS at its serine1177 residue [44,50,51] .…”

Section: Discussionmentioning

confidence: 99%

“…GH and PL induce eNOS phosphorylation at serine 1177 in rat aortic endothelial cells It is well known that vasoactive agents such as vascular endothelial growth factor (VEGF), bradykinin (BK) and ACh activate eNOS [41][42][43][44][45] via the phosphorylation of the serine 1177 residue and the subsequent production of small amounts of NO [44,46,47] . We investigated whether GH and PL stimulate eNOS via the phosphorylation of its serine 1177 residue in cultured aortic endothelial cells.…”

Section: Wwwchinapharcom Gonzalez C Et Almentioning

confidence: 99%

The prolactin family hormones regulate vascular tone through NO and prostacyclin production in isolated rat aortic rings

et al. 2015

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Aim: Prolactin family hormones include growth hormone, placental lactogen and prolactin, which are able to regulate angiogenesis via NO and prostaglandins. However, their effects on vascular tone are not fully understood. The aim of this study was to evaluate the effects of prolactin family hormones on rat vascular tone in vitro. Methods: Aortic rings were prepared from adult male rats and precontracted with phenylephrine, then treated with the hormones and drugs. The tension was measured with isometric force displacement transducer connected to a polygraph. NO production and prostacyclin release in physiological solution was determined. Cultured rat aortic endothelial cells (RAECs) were treated with the hormones and drugs, and the phosphorylation of eNOS at serine 1177 was assessed using Western bolt analysis. Results: Administration of growth hormone or placental lactogen (0.01-100 nmol/L) induced endothelium-dependent vasodilation. Both the hormones significantly increased the phosphorylation of eNOS in RAECs and NO level in physiological solution. Preincubation with L-NAME blocked growth hormone-or placental lactogen-induced vasodilation and NO production. Preincubation with an antibody against growth hormone receptors blocked growth hormone-and placental lactogen-induced vasodilation. Addition of a single dose of prolactin (0.01 nmol/L) induced sustained vessel relaxation, whereas multiple doses of prolactin induced a biphasic contractionrelaxation effect. The vascular effects of prolactin depended on endothelium. Prolactin significantly increased the level of prostacyclin I 2 in physiological solution. Preincubation with indomethacin or an antibody against prolactin receptors blocked prolactin-induced vasodilation. Conclusion: The prolactin family hormones regulate rat vascular tone, selectively promoting either relaxation or contraction of vascular smooth muscle via activation of either growth hormone receptors or prolactin receptors within the endothelium.

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“…La PRL humaine 16K induit aussi l'apoptose par un mécanisme qui nécessite l'activation du facteur nucléaire B (NF-B) [23]. Dans la rétine, les produits de clivage de la PRL inactivent eNOS (endothelial nitric oxide synthase) par l'intermédiaire d'une inactivation de la phosphatase 2A et il a été suggéré qu'ils inhibent ainsi l'activation de la production de NO (nitric oxide) induite par le VEGF [24]. La PRL 16K pourrait exercer des effets anti-angiogénique, vasorelaxant et inhibiteur de la migration sur les cellules endothéliales [25,26].…”

Section: Prl 23 Kda Et 16k Dans Les Tissus De Mammifèresunclassified

La prolactine et son fragment 16 kDa dans les tissus de mammifères

2010

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Vasoinhibins prevent retinal vasopermeability associated with diabetic retinopathy in rats via protein phosphatase 2A–dependent eNOS inactivation

Cited by 60 publications

References 68 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

The prolactin family hormones regulate vascular tone through NO and prostacyclin production in isolated rat aortic rings

La prolactine et son fragment 16 kDa dans les tissus de mammifères

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