June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
The B-isoform of VEGFA-165 Does Not Cause Retinal Neovascularization In Vivo, but Does Trigger Inflammatory Response and Breakdown of the Blood Retinal Barrier.
Author Affiliations & Notes
  • Kenneth P Mitton
    Eye Research Institute, Oakland University, Rochester, MI
  • Roberto Schunemann
    Eye Research Institute, Oakland University, Rochester, MI
    Retina Service, Ophtalmus, Joinville, Brazil
  • Ed Guzman
    Eye Research Institute, Oakland University, Rochester, MI
  • Wendy A Dailey
    Eye Research Institute, Oakland University, Rochester, MI
  • Kimberly A Drenser
    Eye Research Institute, Oakland University, Rochester, MI
    Ophthalmology, William Beaumont Hospital, Royal Oak, MI
  • Mei Cheng
    Eye Research Institute, Oakland University, Rochester, MI
  • Brandon Metcalf
    Eye Research Institute, Oakland University, Rochester, MI
  • Kirsten Laux
    Eye Research Institute, Oakland University, Rochester, MI
  • Camryn DeLooff
    Eye Research Institute, Oakland University, Rochester, MI
  • Michael Thomas Trese
    Eye Research Institute, Oakland University, Rochester, MI
    Ophthalmology, William Beaumont Hospital, Royal Oak, MI
  • Footnotes
    Commercial Relationships Kenneth Mitton, None; Roberto Schunemann, None; Ed Guzman, None; Wendy Dailey, None; Kimberly Drenser, None; Mei Cheng, None; Brandon Metcalf, None; Kirsten Laux, None; Camryn DeLooff, None; Michael Trese, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 808. doi:
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      Kenneth P Mitton, Roberto Schunemann, Ed Guzman, Wendy A Dailey, Kimberly A Drenser, Mei Cheng, Brandon Metcalf, Kirsten Laux, Camryn DeLooff, Michael Thomas Trese, ; The B-isoform of VEGFA-165 Does Not Cause Retinal Neovascularization In Vivo, but Does Trigger Inflammatory Response and Breakdown of the Blood Retinal Barrier.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):808.

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

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Abstract

Purpose: VEGFA’s b-isoforms are reported to counter the angiogenic effects of VEGFA on cultured endothelial cells. There is speculation that the b-isoforms might be used to treat retinal neovascularization in diabetic retinopathy, AMD, ROP, and FEVR. However, while VEGFA b-isoforms cannot bind the NRP-1 co-receptor, they bind and activate VEGFR2. We hypothesize that NRP-1 binding is not required to disrupt the blood retinal barrier (BRB) in vivo, where many cell types contribute to cellular inflammatory response, including: endothelial cells, neurons, glia, and monocytes.

Methods: Intra-vitreal injection, of the Long Evans rat eye, compared the effects of human recombinant VEGFA-165b and VEGFA-165, in vivo. Functional assessment was accomplished by Fluorescein Angiography (FA) and Optical Coherence Tomography (OCT), comparing before and after injections. Real-time PCR gene-expression assays evaluated leukocyte endothelial cell adhesion, tight junction disruption, and macrophage activation.

Results: A single dose of VEGFA-165 (regular isoform) caused sustained dilation of the primary retinal veins at 24 hrs post-injection. Control injections of vehicle into the contralateral eyes had no effect. An equivalent dose of VEGFA-165b dilated retinal veins to the same extent. Co-injection of Aflibercept VEGF-trap blocked vein dilation caused by VEGFA-165b. Vessel dilation resolved slowly by 96 hrs. VEGFA-165b suppressed endogenous Vegfa gene expression (20%), but induced inflammatory response as indicated by the increased expression of the Tnfa, Cxcl1, and Cxcl2 genes (10-100 fold). Activation of leukocyte adhesion was revealed by elevated expression of the Icam1, and Selectin genes (Sele, Selp, Sell). Disruption of endothelial cell tight-junctions was confirmed by decreased Claudin-5 gene expression. Injections of VEGFA-165b twice per week for two weeks sustained chronic vascular dilation that did not resolve between injections. No neovascular growth was detected.

Conclusions: Either VEGFA-165b or VEGFA-165 can disrupt the BRB, therefore this process does not require binding of the NRP-1 co-receptor. Intra-vitreal VEGFA-165b reduced endogenous Vegfa gene expression and multiple doses did not cause neovascularization. However, BRB disruption and robust inflammatory response complicate the potential use of VEGFA b-isoforms to treat neovascularization.

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