1 research outputs found
4‑Hydroxy-7-oxo-5-heptenoic Acid Lactone Induces Angiogenesis through Several Different Molecular Pathways
Oxidative stress
and angiogenesis have been implicated not only
in normal phenomena such as tissue healing and remodeling but also
in many pathological processes. However, the relationships between
oxidative stress and angiogenesis still remain unclear, although oxidative
stress has been convincingly demonstrated to influence the progression
of angiogenesis under physiological and pathological conditions. The
retina is particularly susceptible to oxidative stress because of
its intensive oxygenation and high abundance of polyunsaturated fatty
acyls. In particular, it has high levels of docosahexanoates, whose
oxidative fragmentation produces 4-hydroxy-7-oxo-5-heptenoic acid
lactone (HOHA-lactone). Previously, we found that HOHA-lactone is
a major precursor of 2-(ω-carboxyethyl)Âpyrrole (CEP) derivatives,
which are tightly linked to age-related macular degeneration (AMD).
CEPs promote the pathological angiogenesis of late-stage AMD. We now
report additional mechanisms by which HOHA-lactone promotes angiogenesis.
Using cultured ARPE-19 cells, we observed that HOHA-lactone induces
secretion of vascular endothelial growth factor (VEGF), which is correlated
to increases in reactive oxygen species and decreases in intracellular
glutathione (GSH). Wound healing and tube formation assays provided,
for the first time, in vitro evidence that HOHA-lactone induces the
release of VEGF from ARPE-19 cells, which promotes angiogenesis by
human umbilical vein endothelial cells (HUVEC) in culture. Thus, HOHA-lactone
can stimulate vascular growth through a VEGF-dependent pathway. In
addition, results from MTT and wound healing assays as well as tube
formation experiments showed that GSH-conjugated metabolites of HOHA-lactone
stimulate HUVEC proliferation and promote angiogenesis in vitro. Previous
studies demonstrated that HOHA-lactone, through its CEP derivatives,
promotes angiogenesis in a novel Toll-like receptor 2-dependent manner
that is independent of the VEGF receptor or VEGF expression. The new
studies show that HOHA-lactone also participates in other angiogenic
signaling pathways that include promoting the secretion of VEGF from
retinal pigmented epithelial cells