June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Renin-Angiotensin System (RAS) in Hematopoietic Stem/Progenitor Cells (HS/PC) Predicts Vaso-reparative Dysfunction and Progression of Diabetic Retinopathy (DR)
Author Affiliations & Notes
  • Yaqian Duan
    Department of Integrative and Cellular Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States
    Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Eleni Beli
    Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Sergio Li Calzi
    Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Judith Quigley
    Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Rehae Miller
    Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Leni Moldovan
    Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Tatiana Salazar
    Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Sugata Hazra
    Department of Internal Medicine, University of Utah, Salt Lake City, Utah, United States
  • Jude Al-Sabah
    Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • K V Chalam
    Department of Ophthalmology, University of Florida, Jacksonville, Florida, United States
  • Thao Le Phuong Trinh
    Department of Integrative and Cellular Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States
    Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Ruchi Vyas
    Space Life Sciences Research Branch, NASA Ames Research Center, Moffett Field, California, United States
  • Matthew Murray
    Space Life Sciences Research Branch, NASA Ames Research Center, Moffett Field, California, United States
  • Patricia A Parsons-Wingerter
    Space Life Sciences Research Branch, NASA Ames Research Center, Moffett Field, California, United States
  • Gavin Oudit
    Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
  • Maria B Grant
    Department of Ophthalmology, The Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States
    Department of Integrative and Cellular Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Footnotes
    Commercial Relationships   Yaqian Duan, None; Eleni Beli, None; Sergio Li Calzi, None; Judith Quigley, None; Rehae Miller, None; Leni Moldovan, None; Tatiana Salazar, None; Sugata Hazra, None; Jude Al-Sabah, None; K V Chalam, None; Thao Le Phuong Trinh, None; Ruchi Vyas, None; Matthew Murray, None; Patricia Parsons-Wingerter, None; Gavin Oudit, None; Maria Grant, None
  • Footnotes
    Support  R01 HL110170
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4079. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Yaqian Duan, Eleni Beli, Sergio Li Calzi, Judith Quigley, Rehae Miller, Leni Moldovan, Tatiana Salazar, Sugata Hazra, Jude Al-Sabah, K V Chalam, Thao Le Phuong Trinh, Ruchi Vyas, Matthew Murray, Patricia A Parsons-Wingerter, Gavin Oudit, Maria B Grant; Renin-Angiotensin System (RAS) in Hematopoietic Stem/Progenitor Cells (HS/PC) Predicts Vaso-reparative Dysfunction and Progression of Diabetic Retinopathy (DR). Invest. Ophthalmol. Vis. Sci. 2017;58(8):4079.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : We tested the hypothesis that loss of angiotensin converting enzyme 2 (ACE2) within diabetic HS/PCs would be detrimental to HS/PC reparative function, and alter their ability to contribute to vascular remodeling in human subjects and rodent models of DR.

Methods : Subjects (n=52) were recruited as controls (n=13) or diabetics (n=39) with either no DR, mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR or proliferative DR (PDR). Fluorescein angiograms were analyzed using Vessel Generation Analysis (VESGEN) software in a cohort of subjects. CD34+ HS/PCs were isolated from peripheral blood. RAS gene expression and migration was measured. Diabetic ACE2 knockout (KO)/C57BL/6-Ins2 (Akita) mice at 3, 6 and 9 months of diabetes were compared to age-matched controls. Bone marrow HS/PC populations were analyzed by flow cytometry and migration and proliferation studies performed.

Results : ACE2 gene expression in human CD34+ cells from diabetics without DR was increased compared to controls (p=0.0437). Mas receptor mRNA was also increased in diabetics without DR, but reduced with the onset of NPDR (p=0.0002), suggesting a loss of compensation. DR was associated with CD34+ cell migratory dysfunction, which was restored by activating ACE2-mediated RAS axis. By VESGEN analysis, vessel density measured by several confirming parameters in early NPDR (n=3) was greater than in normal retina (n=6) in both arteries and veins, which suggests active retinal remodeling. ACE2KO-Akita and Akita cohorts showed reduced retinal thickness by optical coherence tomography (OCT) at 9 months of diabetes (p<0.0001). Absence of ACE2 in 9-month Akita mice led to an accelerated increase in acellular capillaries compared to diabetic alone (p=0.0185). Electroretinogram (ERG) in ACE2KO-Akita mice resulted in persistent deterioration of the neural retina. Reparative function studies showed that ACE2KO exacerbated diabetes-induced impairment of lineage-c-kit+ cell migration and proliferative functions as early as 3-month of diabetes (p=0.0019).

Conclusions : Retinopathy and adverse vascular remodeling in subjects with diabetes was associated with a loss of the protective arm of RAS in HS/PCs. Loss of ACE2 exacerbated vascular dysfunction in diabetic mice.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×