# Mechanisms of retinal angiogenesis

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $342,000

## Abstract

Previously we have demonstrated that Src-PLD1-PKCγ-cPLA2 signaling is involved in the modulation of retinal
neovascularization. Our studies have also demonstrated that activation of Pak1-cofilin signaling axis is
required for retinal neovascularization. Furthermore, we have shown that besides VEGFA, VEGFC via CREB-
mediated activation of DLL4-NOTCH1 signaling plays an important role in the enhancement of HRMVEC
migration, proliferation, sprouting and tube formation in vitro in a cell culture model and retinal
neovascularization in vivo in an OIR model. During the course of these studies, we found that both VEGFA and
hypoxia stimulate PKCθ very robustly and depletion of its levels completely blocks the migrating and sprouting
capacity of HRMVECs in response to VEGFA. We have also observed that both VEGFA and hypoxia induce
Flt4 expression profoundly and this response requires PKCθ-mediated JunB induction. Furthermore, both
VEGFA and hypoxia triggered the induction of expression of CDC6, a regulatory component of pre-replication
complex (pre-RC) and involved in loading the mini chromosome maintenance proteins (MCM2-7) onto the
DNA, which plays a rate-limiting step in replication. In addition, down regulation of CDC6 levels completely
abolished VEGFA-induced DNA synthesis. Based on these novel discoveries, we propose that PKCθ via
enhancing EC migration and sprouting and CDC6 via enhancing EC proliferation play an integral role in the
modulation retinal neovascularization. To test this central hypothesis, we will address the following four specific
aims. Aim 1. To test the hypothesis that PKCθ mediates hypoxia-induced retinal neovascularization. Aim 2. To
test the hypothesis that JunB mediates hypoxia-induced retinal neovascularization. Aim 3. To test the
hypothesis that PKCθ-JunB signaling axis targets Flt4 induction in mediating retinal neovascularization. Aim 4.
To test the hypothesis that CDC6 plays an essential role in retinal neovascularization. The results of the
proposed experiments may provide novel information in regard to the molecular mechanisms underling
pathological retinal neovascularization, which could lead to the development of new therapeutic compounds
against this ocular disease.

## Key facts

- **NIH application ID:** 9910397
- **Project number:** 5R01EY014856-14
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** GADIPARTHI N RAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,000
- **Award type:** 5
- **Project period:** 2006-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9910397

## Citation

> US National Institutes of Health, RePORTER application 9910397, Mechanisms of retinal angiogenesis (5R01EY014856-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9910397. Licensed CC0.

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