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Jaeryung Kim, Jang Ryul Park, Hellmut G. Augustin, Yoshiaki Kubota, Tae-Young Chung, Wang-Yuhl Oh, Gou Young Koh; An essential role for angiopoietin-Tie2 signaling in wet age-related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2018;59(9):3264.
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© ARVO (1962-2015); The Authors (2016-present)
The primary aims of this study were to investigate whether the angiopoietin (Ang)-Tie2 system is essential for maintenance of choriocapillaris (CC) during adulthood on concerning the pathogenesis of wet AMD and to evaluate the effect of endothelial receptor Tie2 activation on suppressions of the choroidal neovascularization (CNV) and leakage, and CC regeneration.
We made transgenic mice models depleting Ang1 or Tie2 starting from adulthood and analyzed their CC, photoreceptors, and visual function. Next, we induced CNV by laser injury and analyzed extent of CNV formation and avascular space surrounding the CNV. Then, we administered VEGF-Trap (VT) or a Tie2-activating antibody named ABTAA intravitreally into laser-induced CNV mice. CNV volume, leakage, and CC regeneration were monitored by conventional and optical coherence tomography angiography (OCTA) and changes in gene expression profiles in the CNV and surrounding tissues were analyzed by RNA-sequencing.
While Tie2 was enriched in endothelial cells, Ang1 was enriched in perivascular cells surrounding CC. Conditional Tie2 or Ang1 deletion mice showed the CC density measured by OCTA was reduced by ~20% (p<.01) at 8 weeks after tamoxifen induction, with attenuated photopic b-wave by ~40% (p<.01) and decreased density of cone photoreceptor outer segments by ~41% (p<.05). Moreover, conditional Tie2 deletion mice showed increased CNV volume and avascular space (p<.01, respectively). Meanwhile, both ABTAA and VT suppressed CNV and leakage. Intriguingly, compared with Fc-treated control, ABTAA regenerated CC (p<.01), whereas VT rather increased avascular space (p<.01). The regenerated CC subsequently alleviated hypoxia, leading to a favorable transition of the CNV microenvironment to prevent CNV recurrence.
We demonstrated the crucial role of the Ang-Tie2 system in CC maintenance in the context of wet AMD. The favorable alteration of the CNV microenvironment by ABTAA-induced CC regeneration makes it a novel alternative that can be used to fill in the gaps in current anti-VEGF therapies. Further investigation is needed to evaluate its efficacy and safety in clinical trials.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
En face OCT angiograms showing outer retinal flow showing the CNV (red) and choroidal flow (blue) and avascular space (area demarcated by yellow boundary) surrounding the CNV acquired by longitudinal OCTA imaging of eyes treated with Fc, VT, or ABTAA.
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