July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
The pathogenesis of polypoidal choroidal vasculopathy proceeds via a two-stage process
Author Affiliations & Notes
  • Yingbin Fu
    Ophthalmology, Baylor College of Medicine, Houston, Utah, United States
  • Sandeep Kumar
    Ophthalmology, Baylor College of Medicine, Houston, Utah, United States
  • Hiroyuki Nakashizuka
    Visual Sciences, Nihon University School of Medicine, Tokyo, Japan
  • Alex Jones
    Ophthalmology, University of Utah, Salt Lake City, Utah, United States
  • Alyssia Lambert
    Chemistry, University of Utah, Salt Lake City, Utah, United States
  • Xuchen Zhao
    Chemistry, University of Utah, Salt Lake City, Utah, United States
  • Megan Shen
    Ophthalmology, Baylor College of Medicine, Houston, Utah, United States
  • Mackenzie Parker
    Ophthalmology, Baylor College of Medicine, Houston, Utah, United States
  • Mark O M Tso
    Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Jon Rainier
    Chemistry, University of Utah, Salt Lake City, Utah, United States
  • Footnotes
    Commercial Relationships   Yingbin Fu, University of Utah (R), University of Utah research foundation (application 20140323413) (P); Sandeep Kumar, None; Hiroyuki Nakashizuka, None; Alex Jones, None; Alyssia Lambert, None; Xuchen Zhao, None; Megan Shen, None; Mackenzie Parker, None; Mark O M Tso, None; Jon Rainier, None
  • Footnotes
    Support  NIH grants 5R01EY022901 (YF), 2P30EY002520 (Baylor College of Medicine), 5P30EY014800 (University of Utah), The Sarah Campbell Blaffer Endowment in Ophthalmology (YF), the Career Development Award from Research to Prevent Blindness (RPB) (YF), C. M. Reeves & M. A. Reeves Foundation (YF), Moran Center for Translational Medicine (YF), unrestricted grants to the Department of Ophthalmology at the University of Utah and the Department of Ophthalmology at Baylor College of Medicine from RPB.
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 346. doi:
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    • Get Citation

      Yingbin Fu, Sandeep Kumar, Hiroyuki Nakashizuka, Alex Jones, Alyssia Lambert, Xuchen Zhao, Megan Shen, Mackenzie Parker, Mark O M Tso, Jon Rainier; The pathogenesis of polypoidal choroidal vasculopathy proceeds via a two-stage process. Invest. Ophthalmol. Vis. Sci. 2018;59(9):346.

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

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Abstract

Purpose : PCV is a common subtype of wet AMD in Asian populations while CNV is the typical subtype in Western populations. Although the two subtypes share genetic and risk factors, they have distinct clinical characteristic, natural histories and treatment outcomes. The purposes of this study are to dissect the molecular mechanism underlying the pathogenesis of PCV and to understand the pathological differences between PCV and CNV

Methods : We performed comprehensive genetic, histopathological, imaging, molecular biological, and functional studies to compare an established PCV mouse model expressing protease HTRA1 in retinal pigment epithelium with transgenic mice expressing the inactive HTRA1S328A. We also performed histopathological analysis on human PCV specimens.

Results : We showed that HTRA1 mediated degradation of elastin in choroidal vessels is critical for the development of PCV, which exhibited destructive extracellular matrix remodeling and vascular smooth muscle cell loss. Compared with weak PCV, severe PCV exhibited prominent immune complex deposition, complement activation, increase of pro-inflammatory cytokines, and infiltration of inflammatory cells such as neutrophils and macrophages in lesions, suggesting inflammation plays a key role in PCV progression. In addition to HTRA1, matrix-degrading proteases MMP2 and MMP9 were increased in PCV lesions. Importantly, we validated these findings in human PCV specimens. Intravitreal delivery of an HTRA1 inhibitor (DPMFKLboroV) was effective in preventing PCV initiation but ineffective in treating existing lesions. Anti-inflammatory glucocorticoid was effective in preventing PCV progression but ineffective in preventing PCV initiation. Image-guided focal ERG analysis showed that retinal function (both a and b waves) was attenuated in PCV lesion areas. The biggest reduction occurred in more severe lesions (e.g. big lesions and cluster-type lesions). Interestingly, retinal function in the non-lesion area was also affected although to a less extent than in the lesion area.

Conclusions : PCV pathogenesis occurs through two stages. The initiation stage is mediated by proteolytic degradation of extracellular matrix proteins due to increased HTRA1 activity while the progression stage is driven by inflammatory cascades. This study provides a basis for understanding the differences between PCV and CNV, and helps guide the design of effective therapies for PCV.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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