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Reactive Oxygen Species as Mediators of Angiogenesis
Author(s) -
UshioFukai Masuko
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a21-c
Subject(s) - angiogenesis , nadph oxidase , nox1 , protein kinase b , microbiology and biotechnology , nox4 , biology , reactive oxygen species , vascular endothelial growth factor , p22phox , signal transduction , chemistry , cancer research , vegf receptors
Angiogenesis, a process of new blood vessel formation, is a key process involved in normal development and wound repair, as well as in the various pathophysiologies such as ischemic heart and limb diseases, and atherosclerosis. Reactive oxygen species (ROS) such as superoxide and H2O2 are implicated in the pathophysiology of a variety of cardiovascular diseases including coronary artery disease, heart failure, hypertension, atherosclerosis and diabetes. Although excess amount of ROS have cytotoxic effects, physiological concentration of ROS are implicated in cell signaling activated by growth factors. Accumulating evidence reveals that ROS play an important role in angiogenesis; however, its underlying molecular mechanisms remain unknown. Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating endothelial cell (EC) proliferation and migration primarily through the receptor tyrosine kinase VEGF receptor2 (VEGFR2, Flk1/KDR). VEGF binding initiates tyrosine phosphorylation of VEGFR2, which results in activation of downstream signaling enzymes including ERK1/2, Akt and eNOS, which contribute to angiogenic‐related responses in EC. Importantly, the major source of ROS in EC is a NAD(P)H oxidase (Nox) and EC express Nox1, Nox2 (gp91phox), Nox4, p22phox, p47phox, p67phox and the small G protein Rac1. Because EC migration and proliferation are primary features of the process of angiogenesis, we would like to discuss the molecular mechanisms by which NAD(P)H oxidase‐derived ROS mediate VEGF‐induced signaling linked to EC migration and proliferation as well as postnatal angiogenesis in response to hindlimb ischemia. Understanding these mechanisms may provide insight into the components of NAD(P)H oxidase and their regulators as potential therapeutic targets for treatment of angiogenesis‐dependent diseases.