CELLULAR MECHANISMS OF RETINAL ANGIOGENESIS

Project: Research project

Project Details

Description

The long range goal of this project is to elucidate fundamental
mechanisms of retinal angiogenesis. The overall hypothesis is that
retinal angiogenesis depends on molecular interactions between the
endothelial cell (EC) derived relaxing factor, nitric oxide (NO), its
Ca2+-dependent synthetic enzyme, eNOS and the EC-specific angiogenic
factor vascular endothelial growth factor (VEGF). A working model is
proposed in which VEGF stimulation of its receptors induces NOS
activation and production of NO, which influences EC growth directly by
inducing cell proliferation and indirectly by inhibiting VEGF protein
expression. This model will be developed and refined by experiments in
specific aims designed to test the following specific hypotheses using
a combination of cellular and molecular analytical approaches. 1) VEGF-
induced growth of retinal ECs is mediated by eNOS production of NO.
Experiments using cultured retinal Ecs will determine VEGF effects on
NOS activity, NO production and cell growth in the presence and absence
of NOS inhibitors and of NO onEC growth. 2) Expression of eNOS and VEGF
is regulated by a feed-forward/feed-back relationship in which VEGF
promotes increased eNOS expression and NO production which in turn
inhibits VEGF expression. These experiments will test NO donor effects
on VEGF expression in retinal Ecs and glial cells and VEGF effects on
eNOS expression in retinal ECs. 3) eNOS is directly involved in VEGF
signal transduction to the nucleus. These experiments will determine
the effects of VEGF-stimulation on the subcellular distribution of eNOS,
VEGF and its receptors and test the role of NO in VEGF-induction of gene
transcription in retinal Ecs. 4) eNOS activity has a critical role in
regulating retinal vascular growth and development in vivo. Experiments
in eNOS deficient mice will characterize retinal vascular growth and
development in relation to expression of inducible NOS (iNOS),
constitutive NOS (nNOS) and VEGF.

Information gained from these investigations will aid the development
of therapies to prevent and control pathological angiogenic processes.
StatusFinished
Effective start/end date3/1/982/28/18

ASJC

  • Medicine(all)