Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 656

10.6.15 Oxidative Stress and Inflammation

Inflammation, oxidative stress, and angiogenesis are involved in numerous phys-
iological and pathophysiological processes from healing and remodeling to tu-
morigenesis. Angiogenesis is not only associated with hypoxia, but also with
inflammation-induced oxidation.
Angiogenesis and inflammation are related. Inflammatory cells release pro-
angiogenic growth factors such as VEGF. In turn, newly formed blood vessels
enhance inflammatory cell recruitment. Leukocytes, in particular myeloid cells, are
guided by and contribute to oxidative stress and generation of oxidative products,
such as hydroxy-

-oxoalkenoic acids and their esters [ 1329 ]. Associated with
oxidized phospholipids, these molecules are sensed by scavenger receptors ScaRb3
and contribute to platelet hyper-reactivity. Hydrolysis followed by reaction of the
resulting unesterified hydroxy-

ω

-oxoalkenoic acids with proteins, or conversely re-
action with proteins followed by hydrolysis, creates a family of carboxyalkylpyrrole
protein adducts (CAP). 77

ω

-2-carboxyethylpyrrole
(CEP) and other related pyrroles are generated during inflammation and healing.
Carboxyalkylpyrroles are detected by Toll-like receptor TLR2, but neither by
TLR4 nor by scavenger receptors on endothelial cells. They prime angiogenesis,
independently of vascular endothelial growth factor [ 1329 ]. Toll-like receptor-2 and
its adaptor MyD88 are required for CEP-induced stimulation of Rac1 GTPase and
endothelial migration.
Reactive oxygen species are implicated in stress responses. Reactive oxygen
species in stressed cells can be produced by NADPH oxidases, uncoupled nitric
oxide synthases, and xanthine oxidases. NADPH oxidase NOx4 facilitates cardiac
adaptation to chronic stress [ 1330 ]. Unlike other NOx proteins, NOx4 activity is
regulated mainly by its expression level, which rises in cardiomyocytes subjected
to mechanical and chemical stresses, such as pressure overload or hypoxia. En-
zyme NOx4 enhances stress-induced activation of hypoxia-inducible factor-1 in
cardiomyocytes as well as release of vascular endothelial growth factor for paracrine
angiogenic signaling.

End products of lipid oxidation ω

77 These adducts localize to oxidized low-density lipoprotein and accumulate in atherosclerotic
plaques as well as retina, where they promote choroidal neovascularization and age-related macular
degeneration. These adducts, carboxyethylpyrrole (CEP) in particular, are transiently observed
during wound healing. At injury sites, they reach a maximum concentration 3 days after damage
and return to original levels when the healing is completed. High levels of CEP correlate with
intense vascularization of damaged tissue.