Diabetic eNOS-knockout mice develop accelerated retinopathy

Qiuhong Li, Amrisha Verma, Ping Yang Han, Takahiko Nakagawa, Richard J. Johnson, Maria B. Grant, Martha Campbell-Thompson, Yagna P R Jarajapu, Bo Lei, William W. Hauswirth

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

PURPOSE. Dysfunction of endothelial nitric oxide synthase (eNOS) has been implicated in the pathogenesis of diabetic vascular complications. This study was undertaken to determine the role of eNOS in the development of diabetic retinopathy (DR), by investigating the functional consequences of its deficiency in the diabetic state. METHODS. Diabetes was induced in eNOS-knockout (eNOS-/-) and C57B/6 mice by streptozotocin (STZ) injection. Retinal vasculature was evaluated by albumin extravasation, to quantitatively measure vascular permeability, and by trypsin-digested retinal vascular preparations, to quantify acellular capillaries. Gliosis was evaluated by immunofluorescent techniques. Retinal capillary basement membrane thickness was assessed by transmission electron microscopy. Total retinal nitric oxide level was assessed by measuring nitrate/nitrite using a fluorometricbased assay, iNOS expression was examined by real-time PCR. RESULTS. Diabetic eNOS-/- mice exhibit more severe retinal vascular permeability than age-matched diabetic C57BL/6 mice, detectable as early as 3 weeks after diabetes induction. Diabetic eNOS-/- mice also show earlier onset and an increased number of acellular capillaries, sustained gliosis, and increased capillary basement membrane thickness. Total nitric oxide (NO) level was also increased, concomitant with elevated iNOS expression in diabetic eNOS-/- retina. CONCLUSIONS. Diabetic eNOS-/- mice exhibit A significantly wider range of advanced retinal vascular complications than the age-matched diabetic C57BL/6 mice, supporting the notion that eNOS-derived NO plays an essential role in retinal vascular function. This mouse model also faithfully replicates many of the hallmarks of vascular changes associated with human retinopathy, thus providing a unique model to aid in understanding the pathologic mechanisms of and to develop effective therapeutic strategies for diabetic retinopathy.

Original languageEnglish (US)
Pages (from-to)5240-5246
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume51
Issue number10
DOIs
StatePublished - Oct 2010
Externally publishedYes

Fingerprint

Nitric Oxide Synthase Type III
Knockout Mice
Retinal Vessels
Nitric Oxide
Gliosis
Capillary Permeability
Diabetic Retinopathy
Inbred C57BL Mouse
Basement Membrane
Diabetic Angiopathies
Streptozocin
Nitrites
Transmission Electron Microscopy
Nitrates
Trypsin
Blood Vessels
Retina
Real-Time Polymerase Chain Reaction
Albumins
Injections

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Li, Q., Verma, A., Han, P. Y., Nakagawa, T., Johnson, R. J., Grant, M. B., ... Hauswirth, W. W. (2010). Diabetic eNOS-knockout mice develop accelerated retinopathy. Investigative Ophthalmology and Visual Science, 51(10), 5240-5246. https://doi.org/10.1167/iovs.09-5147

Diabetic eNOS-knockout mice develop accelerated retinopathy. / Li, Qiuhong; Verma, Amrisha; Han, Ping Yang; Nakagawa, Takahiko; Johnson, Richard J.; Grant, Maria B.; Campbell-Thompson, Martha; Jarajapu, Yagna P R; Lei, Bo; Hauswirth, William W.

In: Investigative Ophthalmology and Visual Science, Vol. 51, No. 10, 10.2010, p. 5240-5246.

Research output: Contribution to journalArticle

Li, Q, Verma, A, Han, PY, Nakagawa, T, Johnson, RJ, Grant, MB, Campbell-Thompson, M, Jarajapu, YPR, Lei, B & Hauswirth, WW 2010, 'Diabetic eNOS-knockout mice develop accelerated retinopathy', Investigative Ophthalmology and Visual Science, vol. 51, no. 10, pp. 5240-5246. https://doi.org/10.1167/iovs.09-5147
Li Q, Verma A, Han PY, Nakagawa T, Johnson RJ, Grant MB et al. Diabetic eNOS-knockout mice develop accelerated retinopathy. Investigative Ophthalmology and Visual Science. 2010 Oct;51(10):5240-5246. https://doi.org/10.1167/iovs.09-5147
Li, Qiuhong ; Verma, Amrisha ; Han, Ping Yang ; Nakagawa, Takahiko ; Johnson, Richard J. ; Grant, Maria B. ; Campbell-Thompson, Martha ; Jarajapu, Yagna P R ; Lei, Bo ; Hauswirth, William W. / Diabetic eNOS-knockout mice develop accelerated retinopathy. In: Investigative Ophthalmology and Visual Science. 2010 ; Vol. 51, No. 10. pp. 5240-5246.
@article{ecf5ecdb3efe460c80518833b91b74ae,
title = "Diabetic eNOS-knockout mice develop accelerated retinopathy",
abstract = "PURPOSE. Dysfunction of endothelial nitric oxide synthase (eNOS) has been implicated in the pathogenesis of diabetic vascular complications. This study was undertaken to determine the role of eNOS in the development of diabetic retinopathy (DR), by investigating the functional consequences of its deficiency in the diabetic state. METHODS. Diabetes was induced in eNOS-knockout (eNOS-/-) and C57B/6 mice by streptozotocin (STZ) injection. Retinal vasculature was evaluated by albumin extravasation, to quantitatively measure vascular permeability, and by trypsin-digested retinal vascular preparations, to quantify acellular capillaries. Gliosis was evaluated by immunofluorescent techniques. Retinal capillary basement membrane thickness was assessed by transmission electron microscopy. Total retinal nitric oxide level was assessed by measuring nitrate/nitrite using a fluorometricbased assay, iNOS expression was examined by real-time PCR. RESULTS. Diabetic eNOS-/- mice exhibit more severe retinal vascular permeability than age-matched diabetic C57BL/6 mice, detectable as early as 3 weeks after diabetes induction. Diabetic eNOS-/- mice also show earlier onset and an increased number of acellular capillaries, sustained gliosis, and increased capillary basement membrane thickness. Total nitric oxide (NO) level was also increased, concomitant with elevated iNOS expression in diabetic eNOS-/- retina. CONCLUSIONS. Diabetic eNOS-/- mice exhibit A significantly wider range of advanced retinal vascular complications than the age-matched diabetic C57BL/6 mice, supporting the notion that eNOS-derived NO plays an essential role in retinal vascular function. This mouse model also faithfully replicates many of the hallmarks of vascular changes associated with human retinopathy, thus providing a unique model to aid in understanding the pathologic mechanisms of and to develop effective therapeutic strategies for diabetic retinopathy.",
author = "Qiuhong Li and Amrisha Verma and Han, {Ping Yang} and Takahiko Nakagawa and Johnson, {Richard J.} and Grant, {Maria B.} and Martha Campbell-Thompson and Jarajapu, {Yagna P R} and Bo Lei and Hauswirth, {William W.}",
year = "2010",
month = "10",
doi = "10.1167/iovs.09-5147",
language = "English (US)",
volume = "51",
pages = "5240--5246",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "10",

}

TY - JOUR

T1 - Diabetic eNOS-knockout mice develop accelerated retinopathy

AU - Li, Qiuhong

AU - Verma, Amrisha

AU - Han, Ping Yang

AU - Nakagawa, Takahiko

AU - Johnson, Richard J.

AU - Grant, Maria B.

AU - Campbell-Thompson, Martha

AU - Jarajapu, Yagna P R

AU - Lei, Bo

AU - Hauswirth, William W.

PY - 2010/10

Y1 - 2010/10

N2 - PURPOSE. Dysfunction of endothelial nitric oxide synthase (eNOS) has been implicated in the pathogenesis of diabetic vascular complications. This study was undertaken to determine the role of eNOS in the development of diabetic retinopathy (DR), by investigating the functional consequences of its deficiency in the diabetic state. METHODS. Diabetes was induced in eNOS-knockout (eNOS-/-) and C57B/6 mice by streptozotocin (STZ) injection. Retinal vasculature was evaluated by albumin extravasation, to quantitatively measure vascular permeability, and by trypsin-digested retinal vascular preparations, to quantify acellular capillaries. Gliosis was evaluated by immunofluorescent techniques. Retinal capillary basement membrane thickness was assessed by transmission electron microscopy. Total retinal nitric oxide level was assessed by measuring nitrate/nitrite using a fluorometricbased assay, iNOS expression was examined by real-time PCR. RESULTS. Diabetic eNOS-/- mice exhibit more severe retinal vascular permeability than age-matched diabetic C57BL/6 mice, detectable as early as 3 weeks after diabetes induction. Diabetic eNOS-/- mice also show earlier onset and an increased number of acellular capillaries, sustained gliosis, and increased capillary basement membrane thickness. Total nitric oxide (NO) level was also increased, concomitant with elevated iNOS expression in diabetic eNOS-/- retina. CONCLUSIONS. Diabetic eNOS-/- mice exhibit A significantly wider range of advanced retinal vascular complications than the age-matched diabetic C57BL/6 mice, supporting the notion that eNOS-derived NO plays an essential role in retinal vascular function. This mouse model also faithfully replicates many of the hallmarks of vascular changes associated with human retinopathy, thus providing a unique model to aid in understanding the pathologic mechanisms of and to develop effective therapeutic strategies for diabetic retinopathy.

AB - PURPOSE. Dysfunction of endothelial nitric oxide synthase (eNOS) has been implicated in the pathogenesis of diabetic vascular complications. This study was undertaken to determine the role of eNOS in the development of diabetic retinopathy (DR), by investigating the functional consequences of its deficiency in the diabetic state. METHODS. Diabetes was induced in eNOS-knockout (eNOS-/-) and C57B/6 mice by streptozotocin (STZ) injection. Retinal vasculature was evaluated by albumin extravasation, to quantitatively measure vascular permeability, and by trypsin-digested retinal vascular preparations, to quantify acellular capillaries. Gliosis was evaluated by immunofluorescent techniques. Retinal capillary basement membrane thickness was assessed by transmission electron microscopy. Total retinal nitric oxide level was assessed by measuring nitrate/nitrite using a fluorometricbased assay, iNOS expression was examined by real-time PCR. RESULTS. Diabetic eNOS-/- mice exhibit more severe retinal vascular permeability than age-matched diabetic C57BL/6 mice, detectable as early as 3 weeks after diabetes induction. Diabetic eNOS-/- mice also show earlier onset and an increased number of acellular capillaries, sustained gliosis, and increased capillary basement membrane thickness. Total nitric oxide (NO) level was also increased, concomitant with elevated iNOS expression in diabetic eNOS-/- retina. CONCLUSIONS. Diabetic eNOS-/- mice exhibit A significantly wider range of advanced retinal vascular complications than the age-matched diabetic C57BL/6 mice, supporting the notion that eNOS-derived NO plays an essential role in retinal vascular function. This mouse model also faithfully replicates many of the hallmarks of vascular changes associated with human retinopathy, thus providing a unique model to aid in understanding the pathologic mechanisms of and to develop effective therapeutic strategies for diabetic retinopathy.

UR - http://www.scopus.com/inward/record.url?scp=77958117750&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77958117750&partnerID=8YFLogxK

U2 - 10.1167/iovs.09-5147

DO - 10.1167/iovs.09-5147

M3 - Article

VL - 51

SP - 5240

EP - 5246

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 10

ER -