PUBLICATION

Selective Inhibition of Retinal Angiogenesis by Targeting PI3 Kinase

Authors

Alvarez, Y., Astudillo, O., Jensen, L., Reynolds, A.L., Waghorne, N., Brazil, D.P., Cao, Y., O'Connor, J.J., and Kennedy, B.N.

ID

ZDB-PUB-091120-75

Date

2009

Source

PLoS One 4(11): e7867 (Journal)

Registered Authors

Alvarez, Yolanda, Kennedy, Breandan N.

Keywords

Angiogenesis, Larvae, Zebrafish, Eyes, Vasculogenesis, Lens (anatomy), Blood vessels, Small molecules

MeSH Terms

Retinal Vessels/pathology*
Gene Expression Regulation, Developmental
Inhibitory Concentration 50
Chromones/pharmacology
Gene Expression Regulation, Enzymologic*
Enzyme Inhibitors/pharmacology
Neovascularization, Pathologic*
Zebrafish
Morpholines/pharmacology
Vascular Endothelial Growth Factor A/metabolism
Electroretinography/methods
Time Factors
Animals
Hypoxia
Phosphatidylinositol 3-Kinases/metabolism*
Retina/embryology
Retina/pathology*

(all 17)

PubMed

19924235 Full text @ PLoS One

Abstract

Ocular neovascularisation is a pathological hallmark of some forms of debilitating blindness including diabetic retinopathy, age related macular degeneration and retinopathy of prematurity. Current therapies for delaying unwanted ocular angiogenesis include laser surgery or molecular inhibition of the pro-angiogenic factor VEGF. However, targeting of angiogenic pathways other than, or in combination to VEGF, may lead to more effective and safer inhibitors of intraocular angiogenesis. In a small chemical screen using zebrafish, we identify LY294002 as an effective and selective inhibitor of both developmental and ectopic hyaloid angiogenesis in the eye. LY294002, a PI3 kinase inhibitor, exerts its anti-angiogenic effect in a dose-dependent manner, without perturbing existing vessels. Significantly, LY294002 delivered by intraocular injection, significantly inhibits ocular angiogenesis without systemic side-effects and without diminishing visual function. Thus, targeting of PI3 kinase pathways has the potential to effectively and safely treat neovascularisation in eye disease.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
plxnd1^{unspecified/unspecified}; y1Tg	standard conditions	Day 5	hyaloid vessel branchiness, abnormal	Fig. 5
plxnd1^{unspecified/unspecified}; y1Tg	standard conditions	Day 5	ocular blood vessel increased amount, abnormal	Fig. 5
plxnd1^{unspecified/unspecified}; y1Tg	chemical treatment: LY294002	Day 5	hyaloid vessel branchiness, normal	Fig. 5
y1Tg	chemical treatment: LY294002	Day 5	angiogenesis disrupted, abnormal	Fig. 1
y1Tg	chemical treatment: LY294002	Day 5	hyaloid vessel branchiness, abnormal	Fig. 5
y1Tg	chemical treatment: LY294002	Day 5	hyaloid vessel irregular spatial pattern, abnormal	Fig. 1
y1Tg	chemical treatment: LY294002	Day 5	hyaloid vessel irregular spatial pattern, abnormal	Fig. 4
y1Tg	chemical treatment: LY294002	Day 5	ocular blood vessel decreased amount, abnormal	Fig. 5
y1Tg	chemical treatment: LY294002	Day 5	ocular blood vessel decreased amount, abnormal	Fig. 1
y1Tg	chemical treatment: LY294002	Day 5	ocular blood vessel decreased amount, abnormal	Fig. 4

1 - 10 of 16

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
plxnd1_unspecified		Unspecified	plxnd1
y1Tg	Tg(fli1:EGFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
plxnd1^{unspecified/unspecified}; y1Tg
y1Tg

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Alvarez et al., 2009 ZDB-PUB-091120-75 PMID:19924235

Selective Inhibition of Retinal Angiogenesis by Targeting PI3 Kinase

Alvarez et al., 2009

ZDB-PUB-091120-75
PMID:19924235