Abstract
Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.
Highlights
Angiogenesis is a complex process occurring in physiological situations such as embryogenesis and wound repair, and contributes to pathological conditions such as diabetes, psoriasis, arthritis and cancer
NOX1-deficient mice show impaired angiogenesis In order to test whether NADPH oxidase (NOX)-dependent reactive oxygen species (ROS) production participates in blood vessel formation, we performed in vivo Matrigel angiogenesis assays using mice deficient for different NOX isoforms
To determine whether the aberrant angiogenesis observed in NOX1-deficient mice was due to impaired endothelial cell function; we studied the effect of NOX1 inhibition on mouse lung endothelial cells (MLEC) [27] (Figure S1), murine thymic endothelioma cells and primary human umbilical veinderived endothelial cells (HUVEC)
Summary
Angiogenesis is a complex process occurring in physiological situations such as embryogenesis and wound repair, and contributes to pathological conditions such as diabetes, psoriasis, arthritis and cancer. Angiogenesis is a critical determinant of cancer progression. Stromal cells and infiltrating bone marrow-derived cells can initiate angiogenesis through a process called angiogenic switch in which secretion of proangiogenic factors is increased and/or production of endogenous anti-angiogenic factors is reduced [3,4]. Angiogenic vessels are mostly formed by sprouting of endothelial cells from the existing vasculature. This process involves degradation of the surrounding matrix, cell proliferation, migration, differentiation, and tube formation [5]. Inhibition of angiogenesis has recently been introduced in the clinics as novel therapeutic option to block cancer progression [6]
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