An inhibitor of endothelial ETS transcription factors promotes physiologic and therapeutic vessel regression

Proc Natl Acad Sci U S A. 2020 Oct 20;117(42):26494-26502. doi: 10.1073/pnas.2015980117. Epub 2020 Oct 5.

Abstract

During the progression of ocular diseases such as retinopathy of prematurity and diabetic retinopathy, overgrowth of retinal blood vessels results in the formation of pathological neovascular tufts that impair vision. Current therapeutic options for treating these diseases include antiangiogenic strategies that can lead to the undesirable inhibition of normal vascular development. Therefore, strategies that eliminate pathological neovascular tufts while sparing normal blood vessels are needed. In this study we exploited the hyaloid vascular network in murine eyes, which naturally undergoes regression after birth, to gain mechanistic insights that could be therapeutically adapted for driving neovessel regression in ocular diseases. We found that endothelial cells of regressing hyaloid vessels underwent down-regulation of two structurally related E-26 transformation-specific (ETS) transcription factors, ETS-related gene (ERG) and Friend leukemia integration 1 (FLI1), prior to apoptosis. Moreover, the small molecule YK-4-279, which inhibits the transcriptional and biological activity of ETS factors, enhanced hyaloid regression in vivo and drove Human Umbilical Vein Endothelial Cells (HUVEC) tube regression and apoptosis in vitro. Importantly, exposure of HUVECs to sheer stress inhibited YK-4-279-induced apoptosis, indicating that low-flow vessels may be uniquely susceptible to YK-4-279-mediated regression. We tested this hypothesis by administering YK-4-279 to mice in an oxygen-induced retinopathy model that generates disorganized and poorly perfused neovascular tufts that mimic human ocular diseases. YK-4-279 treatment significantly reduced neovascular tufts while sparing healthy retinal vessels, thereby demonstrating the therapeutic potential of this inhibitor.

Keywords: ERG; FLI1; YK-4-279; hyaloid vessels; oxygen-induced retinopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Blood Vessels / pathology
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Eye / blood supply*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Indoles / pharmacology
  • Mice
  • Oncogene Proteins / metabolism*
  • Oxygen / metabolism
  • Proto-Oncogene Protein c-fli-1 / metabolism*
  • Proto-Oncogene Proteins c-ets / antagonists & inhibitors
  • Proto-Oncogene Proteins c-ets / metabolism
  • Retinal Vessels / pathology
  • Transcriptional Regulator ERG / metabolism*

Substances

  • Angiogenesis Inhibitors
  • ERG protein, mouse
  • Fli1 protein, mouse
  • Indoles
  • Oncogene Proteins
  • Proto-Oncogene Protein c-fli-1
  • Proto-Oncogene Proteins c-ets
  • Transcriptional Regulator ERG
  • YK 4-279
  • Oxygen