July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Endothelial Nox4 Deletion Mitigates Retinal Vascular Abnormalities in Diabetes
Author Affiliations & Notes
  • Sarah Xin Zhang
    Department of Ophthalmology and Ross Eye Institute, University at Buffalo, State University of New York, Buffalo, New York, United States
  • Xixiang Tang
    Department of Ophthalmology and Ross Eye Institute, University at Buffalo, State University of New York, Buffalo, New York, United States
    VIP Center, The Third Affiliated Hospital, Sun Yat-sen University, China
  • Hanna E Abboud
    Department of Medicine, South Texas Veterans Healthcare System and the University of Texas Health Science Center, San Antonio, Texas, United States
  • Yanming Chen
    Division of Endocrinology, The Third Affiliated Hospital, Sun Yat-sen University, China
  • Joshua Jianxin Wang
    Department of Ophthalmology and Ross Eye Institute, University at Buffalo, State University of New York, Buffalo, New York, United States
    SUNY Eye Institute, State University of New York, New York, United States
  • Footnotes
    Commercial Relationships   Sarah Zhang, None; Xixiang Tang, None; Hanna Abboud, None; Yanming Chen, None; Joshua Wang, None
  • Footnotes
    Support  NIH/NEI grants EY019949 and EY025061, and an Unrestricted Grant to the Department of Ophthalmology, SUNY-Buffalo, from Research to Prevent Blindness.
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 2731. doi:
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      Sarah Xin Zhang, Xixiang Tang, Hanna E Abboud, Yanming Chen, Joshua Jianxin Wang; Endothelial Nox4 Deletion Mitigates Retinal Vascular Abnormalities in Diabetes. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2731.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : NADPH oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in endothelial cells (ECs), but its roles in regulation of endothelial function and vascular injury during diabetes remain controversial. Using EC-specific Nox4 knockout (Nox4EC-KO) mice, in which Nox4 was conditionally deleted in ECs, and EC-specific Nox4 transgenic (Nox4EC-Tg) mice that overexpress human Nox4 in ECs, we examined the function of endothelial Nox4 in the development of vascular pathologies in diabetic retinopathy.

Methods : Nox4EC-KO mice and Nox4EC-Tg mice were generated by crossing Nox4 floxed mice or lox-Stop-lox-human Nox4 Tg mice with Tie2-cre mice. Diabetes was induced with streptozotocin in mice at age of 8 weeks. Retinal vascular morphology and vascular permeability were examined by fluorescence angiography, immunostaining, and FITC-dextran methods. Retinal acellular capillary formation was assessed by double staining of retinal whole mounts with anti-Collagen IV antibody and Alexa Fluor 594-conjugated isolectin GS B4. ROS generation and apoptosis were examined in mouse brain microvascular ECs (BMECs).

Results : Successful deletion or overexpression of Nox4 in ECs was confirmed by measuring Nox4 mRNA and protein levels as well as by assessing ROS in BMECs isolated from Nox4EC-KO mice and Nox4EC-Tg mice. At 3 months after hyperglycemia onset, diabetic WT mice demonstrated a 5-fold increase in retinal vascular permeability compared to non-diabetic controls and this increase was blunted in Nox4EC-KO mice. At 6 months after diabetes, a significant increase in acellular capillary formation was observed in diabetic WT mice but not in Nox4EC-KO mice. There was no significant difference in vascular permeability and acellular capillaries between non-diabetic Nox4EC-KO mice and non-diabetic WT mice. In contrast, Nox4EC-Tg mice at ages of 10 – 12 months exhibited increased tortuosity of retinal blood vessels, focal vascular leakage, and acellular capillary formation, compared to age-matched WT mice. In vitro study confirmed enhanced apoptosis and cellular senescence in BMECs derived from Nox4EC-Tg mice.

Conclusions : Our study provides strong in vivo evidence that Nox4 upregulation in retinal ECs is essential for diabetes-induced vascular leakage and acellular capillary formation. Inhibition of Nox4 overactivation in ECs may provide a new approach for the treatment of diabetic vasculopathy in the retina.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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