Molecular pathogenesis of retinal and choroidal vascular diseases

Research output: Contribution to journalArticle

Abstract

There are two major types of ocular neovascularization that affect the retina, retinal neovascularization (NV) and subretinal or choroidal NV. Retinal NV occurs in a group of diseases referred to as ischemic retinopathies in which damage to retinal vessels results in retinal ischemia. Most prevalent of these are diabetic retinopathy and retinal vein occlusions. Subretinal and choroidal NV occur in diseases of the outer retina and Bruch's membrane, the most prevalent of which is age-related macular degeneration. Numerous studies in mouse models have helped to elucidate the molecular pathogenesis underlying retinal, subretinal, and choroidal NV. There is considerable overlap because the precipitating event in each is stabilization of hypoxia inducible factor-1 (HIF-1) which leads to upregulation of several hypoxia-regulated gene products, including vascular endothelial growth factor (VEGF), angiopoietin 2, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and several others. Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal, subretinal, and choroidal NV, with perturbation of Bruch's membrane also needed for the latter. Additional HIF-1-regulated gene products cause further stimulation of the NV. It is difficult to model macular edema in animals and therefore proof-of-concept clinical trials were done and demonstrated that VEGF plays a central role and that suppression of Tie2 is also important. Neutralization of VEGF is currently the first line therapy for all of the above disease processes, but new treatments directed at some of the other molecular targets, particularly stabilization of Tie2, are likely to provide additional benefit for subretinal/choroidal NV and macular edema. In addition, the chronicity of these diseases as well as the implication of VEGF as a cause of retinal nonperfusion and progression of background diabetic retinopathy make sustained delivery approaches for VEGF antagonists a priority.

Original languageEnglish (US)
Pages (from-to)67-81
Number of pages15
JournalProgress in Retinal and Eye Research
Volume49
DOIs
StatePublished - 2015

Fingerprint

Choroid Diseases
Retinal Vessels
Choroidal Neovascularization
Vascular Diseases
Retinal Neovascularization
Vascular Endothelial Growth Factor A
Class 3 Receptor-Like Protein Tyrosine Phosphatases
Angiopoietin-2
Bruch Membrane
Hypoxia-Inducible Factor 1
Macular Edema
Diabetic Retinopathy
Retina
Retinal Vein Occlusion
Macular Degeneration
Genes
Up-Regulation
Ischemia
Clinical Trials

Keywords

  • Age-related macular degeneration
  • Angiogenesis
  • Angiopoietins
  • Diabetic retinopathy
  • Hypoxia-inducible factor-1
  • Platelet-derived growth factor
  • TIE2
  • Vascular endothelial growth factor
  • Vascular endothelial-protein tyrosine phosphatase

ASJC Scopus subject areas

  • Sensory Systems
  • Ophthalmology

Cite this

Molecular pathogenesis of retinal and choroidal vascular diseases. / Campochiaro, Peter A.

In: Progress in Retinal and Eye Research, Vol. 49, 2015, p. 67-81.

Research output: Contribution to journalArticle

@article{d2aad2d5210549eb97d8b78796e0f08f,
title = "Molecular pathogenesis of retinal and choroidal vascular diseases",
abstract = "There are two major types of ocular neovascularization that affect the retina, retinal neovascularization (NV) and subretinal or choroidal NV. Retinal NV occurs in a group of diseases referred to as ischemic retinopathies in which damage to retinal vessels results in retinal ischemia. Most prevalent of these are diabetic retinopathy and retinal vein occlusions. Subretinal and choroidal NV occur in diseases of the outer retina and Bruch's membrane, the most prevalent of which is age-related macular degeneration. Numerous studies in mouse models have helped to elucidate the molecular pathogenesis underlying retinal, subretinal, and choroidal NV. There is considerable overlap because the precipitating event in each is stabilization of hypoxia inducible factor-1 (HIF-1) which leads to upregulation of several hypoxia-regulated gene products, including vascular endothelial growth factor (VEGF), angiopoietin 2, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and several others. Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal, subretinal, and choroidal NV, with perturbation of Bruch's membrane also needed for the latter. Additional HIF-1-regulated gene products cause further stimulation of the NV. It is difficult to model macular edema in animals and therefore proof-of-concept clinical trials were done and demonstrated that VEGF plays a central role and that suppression of Tie2 is also important. Neutralization of VEGF is currently the first line therapy for all of the above disease processes, but new treatments directed at some of the other molecular targets, particularly stabilization of Tie2, are likely to provide additional benefit for subretinal/choroidal NV and macular edema. In addition, the chronicity of these diseases as well as the implication of VEGF as a cause of retinal nonperfusion and progression of background diabetic retinopathy make sustained delivery approaches for VEGF antagonists a priority.",
keywords = "Age-related macular degeneration, Angiogenesis, Angiopoietins, Diabetic retinopathy, Hypoxia-inducible factor-1, Platelet-derived growth factor, TIE2, Vascular endothelial growth factor, Vascular endothelial-protein tyrosine phosphatase",
author = "Campochiaro, {Peter A}",
year = "2015",
doi = "10.1016/j.preteyeres.2015.06.002",
language = "English (US)",
volume = "49",
pages = "67--81",
journal = "Progress in Retinal and Eye Research",
issn = "1350-9462",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Molecular pathogenesis of retinal and choroidal vascular diseases

AU - Campochiaro, Peter A

PY - 2015

Y1 - 2015

N2 - There are two major types of ocular neovascularization that affect the retina, retinal neovascularization (NV) and subretinal or choroidal NV. Retinal NV occurs in a group of diseases referred to as ischemic retinopathies in which damage to retinal vessels results in retinal ischemia. Most prevalent of these are diabetic retinopathy and retinal vein occlusions. Subretinal and choroidal NV occur in diseases of the outer retina and Bruch's membrane, the most prevalent of which is age-related macular degeneration. Numerous studies in mouse models have helped to elucidate the molecular pathogenesis underlying retinal, subretinal, and choroidal NV. There is considerable overlap because the precipitating event in each is stabilization of hypoxia inducible factor-1 (HIF-1) which leads to upregulation of several hypoxia-regulated gene products, including vascular endothelial growth factor (VEGF), angiopoietin 2, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and several others. Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal, subretinal, and choroidal NV, with perturbation of Bruch's membrane also needed for the latter. Additional HIF-1-regulated gene products cause further stimulation of the NV. It is difficult to model macular edema in animals and therefore proof-of-concept clinical trials were done and demonstrated that VEGF plays a central role and that suppression of Tie2 is also important. Neutralization of VEGF is currently the first line therapy for all of the above disease processes, but new treatments directed at some of the other molecular targets, particularly stabilization of Tie2, are likely to provide additional benefit for subretinal/choroidal NV and macular edema. In addition, the chronicity of these diseases as well as the implication of VEGF as a cause of retinal nonperfusion and progression of background diabetic retinopathy make sustained delivery approaches for VEGF antagonists a priority.

AB - There are two major types of ocular neovascularization that affect the retina, retinal neovascularization (NV) and subretinal or choroidal NV. Retinal NV occurs in a group of diseases referred to as ischemic retinopathies in which damage to retinal vessels results in retinal ischemia. Most prevalent of these are diabetic retinopathy and retinal vein occlusions. Subretinal and choroidal NV occur in diseases of the outer retina and Bruch's membrane, the most prevalent of which is age-related macular degeneration. Numerous studies in mouse models have helped to elucidate the molecular pathogenesis underlying retinal, subretinal, and choroidal NV. There is considerable overlap because the precipitating event in each is stabilization of hypoxia inducible factor-1 (HIF-1) which leads to upregulation of several hypoxia-regulated gene products, including vascular endothelial growth factor (VEGF), angiopoietin 2, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and several others. Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal, subretinal, and choroidal NV, with perturbation of Bruch's membrane also needed for the latter. Additional HIF-1-regulated gene products cause further stimulation of the NV. It is difficult to model macular edema in animals and therefore proof-of-concept clinical trials were done and demonstrated that VEGF plays a central role and that suppression of Tie2 is also important. Neutralization of VEGF is currently the first line therapy for all of the above disease processes, but new treatments directed at some of the other molecular targets, particularly stabilization of Tie2, are likely to provide additional benefit for subretinal/choroidal NV and macular edema. In addition, the chronicity of these diseases as well as the implication of VEGF as a cause of retinal nonperfusion and progression of background diabetic retinopathy make sustained delivery approaches for VEGF antagonists a priority.

KW - Age-related macular degeneration

KW - Angiogenesis

KW - Angiopoietins

KW - Diabetic retinopathy

KW - Hypoxia-inducible factor-1

KW - Platelet-derived growth factor

KW - TIE2

KW - Vascular endothelial growth factor

KW - Vascular endothelial-protein tyrosine phosphatase

UR - http://www.scopus.com/inward/record.url?scp=84960482943&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960482943&partnerID=8YFLogxK

U2 - 10.1016/j.preteyeres.2015.06.002

DO - 10.1016/j.preteyeres.2015.06.002

M3 - Article

C2 - 26113211

AN - SCOPUS:84960482943

VL - 49

SP - 67

EP - 81

JO - Progress in Retinal and Eye Research

JF - Progress in Retinal and Eye Research

SN - 1350-9462

ER -