Vascular Endothelial Growth Factor Signaling in Models of Oxygen-Induced Retinopathy: Insights Into Mechanisms of Pathology in Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide. Blindness can occur from retinal detachment caused by pathologic retinal angiogenesis into the vitreous, termed intravitreal neovascularization (IVNV). Although agents that interfere with the bioactivity of vascular endothelial growth factor (VEGF) are now used to treat IVNV, concerns exist regarding the identification of optimal doses of anti-VEGF for individual infants and the effect of broad VEGF inhibition on physiologic angiogenesis in external organs or in the retina of a preterm infant. Therefore, it is important to understand VEGF signaling in both physiologic and pathologic angiogenesis in the retina. In this manuscript, we review the role of receptors that interact with VEGF in oxygen-induced retinopathy (OIR) models that represent features of ROP pathology. Specifically, we discuss our work regarding the regulation of VEGFR2 signaling in retinal endothelial cells to not only reduce severe ROP but also facilitate physiologic retinal vascular and neuronal development.

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The Nrf2 inhibitor brusatol has a protective role in a rat model of oxygen-induced retinopathy of prematurity

Visual Neuroscience ◽

10.1017/s095252382100002x ◽

2021 ◽

Vol 38 ◽

Author(s):

Xiuying Liang ◽

Ruifen Wang

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Rat Model ◽

Retinopathy Of Prematurity ◽

Related Factor ◽

Vascular Endothelial ◽

Down Regulation ◽

Oxygen Induced Retinopathy ◽

Vessel Morphology ◽

Endothelial Growth Factor

Abstract Nuclear factor-erythroid 2-related factor 2 (Nrf2) has been testified to be involved in the development of retinopathy of prematurity (ROP), which can cause childhood visual impairment. Whether brusatol, an Nrf2 inhibitor, could be utilized to treat ROP was unknown. The oxygen-induced retinopathy rat model was established to mimic ROP, which was further intravitreal administrated with brusatol. Vessel morphology and microglial activation in the retina were assessed with histology analysis. The relative expression levels of angiogenesis and inflammation-related molecules were detected with Western blot and real-time polymerase chain reaction methods. Intravitreal brusatol administration could alleviate both angiogenesis and microgliosis induced by hyperoxia, along with down-regulation of vascular endothelial growth factor, vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, cluster of differentiation molecule 11B, tumor necrosis factor alpha, inducible nitric oxide synthase, glial fibrillary acidic protein, and IBA-1 expression. It was further revealed that Nrf2 and heme oxygenease-1 were diminished by brusatol administration. The results demonstrate the potential of intravitreal brusatol deliver to treat ROP with down-regulation of angiogenesis and microgliosis.

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PRH/Hhex Controls Cell Survival through Coordinate Transcriptional Regulation of Vascular Endothelial Growth Factor Signaling

Molecular and Cellular Biology ◽

10.1128/mcb.01511-09 ◽

2010 ◽

Vol 30 (9) ◽

pp. 2120-2134 ◽

Cited By ~ 27

Author(s):

Peter Noy ◽

Hannah Williams ◽

Anyaporn Sawasdichai ◽

Kevin Gaston ◽

Padma-Sheela Jayaraman

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Vegf Receptor ◽

Homeodomain Protein ◽

Growth Factor Signaling ◽

Vascular Endothelial ◽

Promoter Regions ◽

Control Of Gene Expression ◽

Vegf Signaling ◽

Endothelial Growth Factor

ABSTRACT The proline-rich homeodomain protein (PRH) plays multiple roles in the control of gene expression during embryonic development and in the adult. Vascular endothelial growth factor (VEGF) is a mitogen that stimulates cell proliferation and survival via cell surface receptors including VEGFR-1 and VEGFR-2. VEGF signaling is of critical importance in angiogenesis and hematopoiesis and is elevated in many tumors. Here we show that PRH binds directly to the promoter regions of the Vegf, Vegfr-1, and Vegfr-2 genes and that in each case PRH represses transcription. We demonstrate that overexpression or knockdown of PRH directly impinges on the survival of both leukemic and tumor cells and that the modulation of VEGF and VEGF receptor signaling by PRH mediates these effects. Our findings demonstrate that PRH is a key regulator of the VEGF signaling pathway and describe a mechanism whereby PRH plays an important role in tumorigenesis and leukemogenesis.

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Dynamics of Intraocular Pressure after Intravitreal Injection of Vascular Endothelial Growth Factor Inhibitors in Retinopathy of Prematurity

Russian ophthalmology of children ◽

10.25276/2307-6658-2020-2-31-36 ◽

2020 ◽

pp. 31-36

Author(s):

Е.Е. Sidorenko ◽

◽

S.А. Obrubov ◽

Е.I. Sidorenko ◽

N.S. Levina ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Intraocular Pressure ◽

Growth Factor ◽

Intravitreal Injection ◽

Retinopathy Of Prematurity ◽

Vascular Endothelial ◽

Endothelial Growth Factor

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Faculty Opinions recommendation of MicroRNA-10 regulates the angiogenic behavior of zebrafish and human endothelial cells by promoting vascular endothelial growth factor signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717957529.793461935 ◽

2012 ◽

Author(s):

Paul Evans ◽

Jovana Serbanovic-Canic

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Growth Factor Signaling ◽

Vascular Endothelial ◽

Human Endothelial Cells ◽

Endothelial Growth Factor

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Screening auf Frühgeborenenretinopathie – die wichtigsten Änderungen in der neuen deutschen Leitlinie 2020

Der Ophthalmologe ◽

10.1007/s00347-021-01393-6 ◽

2021 ◽

Author(s):

Jeany Q. Li ◽

Ulrich Kellner ◽

Birgit Lorenz ◽

Andreas Stahl ◽

Tim U. Krohne

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Retinopathy Of Prematurity ◽

Vascular Endothelial ◽

Anti Vegf ◽

Zone Ii ◽

Endothelial Growth Factor ◽

Rop Screening

Zusammenfassung Hintergrund Durch Verbesserungen in der neonatologischen Versorgung von Frühgeborenen und die Entwicklung neuer Behandlungsmöglichkeiten der Frühgeborenenretinopathie („retinopathy of prematurity“ [ROP]) haben sich die Anforderungen an das ROP-Screening seit der Veröffentlichung der letzten Fassung der deutschen Leitlinie zum ROP-Screening im Jahr 2008 verändert. Auf Grundlage aktueller Studiendaten wurde die Leitlinie in 2020 grundlegend überarbeitet und in einer aktualisierten Fassung veröffentlicht. Ziel Dieser Artikel fasst die wichtigsten Änderungen in der neuen Leitlinie zusammen. Ergebnisse Die Altersgrenze für einen Screeningeinschluss wurde für Kinder ohne zusätzliche Risikofaktoren auf ein Gestationsalter von unter 31 Wochen gesenkt. Die Mindestdauer für eine Sauerstoffsupplementation, die einen Einschluss in das Screening bei Frühgeborenen erforderlich macht, wurde auf über 5 Tage angehoben. Eine Behandlung bei ROP in Zone II kann nun schon bei jedem Stadium 3 mit Plus-Symptomatik unabhängig von der Anzahl der betroffenen Uhrzeiten erfolgen. Für die Nachkontrollen nach Anti-VEGF („vascular endothelial growth factor“)-Therapie wurden Kriterien zur Frequenz und Dauer definiert. Das verbindliche Dokument für diese und weitere neue Empfehlungen ist die Leitlinie selber. Schlussfolgerungen Die Empfehlungen der Leitlinie ermöglichen eine zuverlässige Identifikation von Kindern mit ROP-Risiko für den Einschluss in das Screening und eine rechtzeitige Erkennung fortgeschrittener Krankheitsstadien für die Therapieeinleitung, um so Erblindung durch ROP zu verhindern.

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Human Chorionic Gonadotropin Induces Nestin Expression in Endothelial Cells of the Ovary via Vascular Endothelial Growth Factor Signaling

Endocrinology ◽

10.1210/en.2007-0774 ◽

2007 ◽

Vol 149 (1) ◽

pp. 253-260 ◽

Cited By ~ 10

Author(s):

Noriyuki Takahashi ◽

Masanori T. Itoh ◽

Bunpei Ishizuka

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Chorionic Gonadotropin ◽

Growth Factor Signaling ◽

Vascular Endothelial ◽

Nestin Expression ◽

Capillary Endothelial Cells ◽

Theca Interna ◽

Endothelial Growth Factor

The intermediate filament protein nestin was originally found to be expressed in neuronal progenitor cells, but recent studies have shown that other cell types, including endocrine and vascular endothelial cells, express nestin. In the present study, we examined the expression and localization of nestin in the ovaries of developing, peripubertal, and adult rats. RT-PCR and Western blot analyses revealed that nestin mRNA and proteins were expressed in adult rat ovaries. Immunohistochemical analyses using adult rat ovaries showed that nestin was mainly localized to capillary endothelial cells of theca interna in follicles with more than two layers of granulosa cells and that its expression increased with follicle growth. Ontogenetically, ovarian nestin expression started at the peripubertal period when the first gonadotropin surge occurs. To test the possibility that gonadotropins induce nestin expression, prepubertal (postnatal d 21) rats were sc injected with equine chorionic gonadotropin (eCG) and/or human chorionic gonadotropin (hCG). A single injection of hCG, but not eCG, was sufficient to induce nestin expression in follicles, mainly in capillary endothelial cells of theca interna. Furthermore, pretreatment with an inhibitor of vascular endothelial growth factor receptor prevented the induction of the nestin expression by hCG. These findings demonstrate that the endogenous LH surge induces nestin expression in capillary endothelial cells of theca interna via the vascular endothelial growth factor signaling pathway. Nestin may be involved in angiogenesis in growing follicles, which is followed by follicle maturation and subsequent ovulation.

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Abstract 168: Contribution of Vascular Endothelial Growth Factor Signaling to Fate Specification in Cardiomyocytes

Circulation Research ◽

10.1161/res.115.suppl_1.168 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Taylor Y Lu ◽

Courtney K Domigan ◽

Vaspour Antanesian ◽

Yasuhiro Nakashima ◽

Atsushi Nakano ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Cell Fate ◽

Heart Development ◽

Embryonic Stem ◽

Growth Factor Signaling ◽

Vascular Endothelial ◽

Rt Pcr ◽

Cardiac Morphogenesis ◽

Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is one of the pivotal proangiogenic growth factors that has long contributed to our knowledge of blood vessel and circulatory maintenance as well as angiogenesis in both pathology and pathophysiology. However, the non-canonical functions of VEGF in cardiac morphogenesis have not been well characterized. Here, we examined how VEGF regulates cardiomyocyte cell fate. Using chimeric embryos harboring both wild type and VEGF-null embryonic stem cells, we observed that derivatives of VEGF null cells were preferentially recruited to the atrium of the heart in comparison to the ventricles. To further provide physiologic context of this finding, we used reporter-LacZ staining and RT-PCR and found that endogenous VEGF was indeed expressed at much lower levels in the atrium but highly expressed in the ventricle early in cardiac morphogenesis. These data lead to our hypothesis that cell-autonomous expression of VEGF is a determinant of atrial vs. ventricular cardiomyocyte cell fate. To test this hypothesis, we used a VEGF knock-in mouse model of Sm22Cre x Rosa 26 VEGF. VEGF overexpression in cardiomyocytes (and smooth muscle) at E8.5 resulted in lethality by P1 and thickened atrial and ventricular walls in mutant embryos as characterized by histology (H&E, IF). We further explored the molecular changes underlying this phenotype via microarray and RT-PCR and find disruptions in molecular markers necessary for wall development, specifically: Notch-1, BMP10, Nrg-1. Taken together, our data indicates that aberrant embryonic VEGF signaling disrupts several critical signaling pathways and that overexpression leads to disruption of cardiomyocyte proliferation and cardiac morphogenesis. These findings add to the foundation of better understanding heart development, laying the groundwork for future therapy of congenital and acquired cardiac disease.

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