Retinal VEGF-a overexpression is not sufficient to induce lymphangiogenesis regardless of VEGF-C upregulation and Lyve1+ macrophage infiltration

Iori Wada, shintaro nakao, Muneo Yamaguchi, Yoshihiro Kaizu, Mitsuru Arima, Shinichiro Sawa, Koh Hei Sonoda

Research output: Contribution to journalArticlepeer-review

Abstract

PURPOSE. No lymphatic vessels have been identified in the retina. This study investigated whether pathological VEGF-A–overexpressing diabetic retina causes lymphangiogenesis. METHODS. Three genetic mouse models of diabetic retinopathy (DR) (Akita [Ins2+/-], Kimba [vegfa+/+], and Akimba [Akita × Kimba] mice) were used. Retinas were examined by fundus photography, fluorescence angiography (FA), and immunostaining to detect lymphangiogenesis or angiogenesis. Lyve1-GFP (Lyve1EGFP/Cre) mice were used to examine Lyve1-expressing cells by immunostaining. Lymphatic-related factors were investigated in mouse retina and vitreous fluid from proliferative diabetic retinopathy (PDR) patients by RT-PCR and ELISA, respectively. Aged Kimba and Akimba mice were used to examine the retinal phenotype at the late phase of VEGF overexpression. RESULTS. FA and immunostaining showed retinal neovascularization in Kimba and Akimba mice but not wild-type and Akita mice. Immunohistochemistry showed that lymphangiogenesis was not present in the retinas of Akita, Kimba, or Akimba mice despite the significant upregulation of lymphatic-related factors (Lyve1, podoplanin, VEGF-A, VEGFC, VEGF-D, VEGFR2, and VEGFR3) in the retinas of Kimba and Akimba mice by RT-PCR (P < 0.005). Furthermore, lymphangiogenesis was not present in aged Kimba or Akimba mice. Significantly increased numbers of Lyve1-positive cells present in the retinas of Kimba and Akimba mice, especially in the peripheral areas, were CD11b positive, indicating a macrophage population (P < 0.005). VEGF-C in PDR vitreous with vitreous hemorrhage (VH) was higher than in PDR without VH or a macular hole. CONCLUSIONS. Retinal VEGF-A overexpression did not cause typical lymphangiogenesis despite upregulated lymphatic-related factors and significant Lyve1-positive macrophage infiltration.

Original languageEnglish
Article number17
JournalInvestigative Ophthalmology and Visual Science
Volume62
Issue number13
DOIs
Publication statusPublished - Oct 2021

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Retinal VEGF-a overexpression is not sufficient to induce lymphangiogenesis regardless of VEGF-C upregulation and Lyve1<sup>+</sup> macrophage infiltration'. Together they form a unique fingerprint.

Cite this