Kou, Baijun, Ni, Jinsong, Vatish, Manu and Singer, Donald R. J.. (2008) Xanthine oxidase interaction with vascular endothelial growth factor in human endothelial cell angiogenesis. Microcirculation, Volume 15 (Number 3). pp. 251-267. ISSN 1073-9688

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Abstract

Objectives: Reduced capillary density occurs early in cardiovascular diseases. Oxidant stress, is implicated in endothelial apoptosis. We investigated the effects of xanthine oxidase (XO) on endothelial survival signaling: protein kinase B/Akt, its cross-talk with p38 MAPK and apoptosis pathways, and its effect on vascular tube formation in vascular endothelial growth factor (VEGF)-simulated human umbilical vein cells. Methods: We studied primary cultured human endothelial cells from the umbilical cord. Reactive oxygen species (ROS) production was detected by dibydroethidium staining, cell-signaling pathways by western blots, cell survival by western blots, and nuclear chromatin and angiogenesis response by MTT proliferation assay and three-dimensional Matrigel cultures. Results: Exogenous XO increased cellular ROS production and caused superoxide-dependent inhibition of Akt phosphorylation and enhancement of p38 MAPK phosphorylation in a time- and dose-dependent mariner. In contrast, application of the XO inhibitor oxypurinol or allopurinol inhibited VEGF-stimulated Akt phosphorylation, indicating that endogenous XO promotes VEGF-induced endothelial cell (EC) survival signaling. Exogenous XO induced activation of caspase-3 and reduced expression of the anti-apoptosis protein Bcl-2. Exogenous XO also reduced EC viability, proliferation, and vascular tube formation by p38 MAPK-dependent, phospboinositide 3-kinase (P13-K) reversible mechanisms; whereas VEGF promoted EC survival by PT3-K-dependent, p38 MAPK-independent effects. Conclusions: Exogenous XO activity is an important contributor to endothelial mechanisms for microvascular rarefaction., by modulation of cell survival signaling pathways; however, endogenons XO is necessary for maintaining EC survival.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School > Metabolic and Vascular Health Faculty of Medicine > Warwick Medical School > Reproductive Health Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Neovascularization, Oxidative stress, Cellular signal transduction, Phosphorylation, Endothelial cells, Vascular endothelial growth factors, Xanthine
Journal or Publication Title:	Microcirculation
Publisher:	John Wiley & Sons Ltd.
ISSN:	1073-9688
Date:	April 2008
Volume:	Volume 15
Number:	Number 3
Number of Pages:	17
Page Range:	pp. 251-267
Identification Number:	10.1080/1073968070165149
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
URI:	http://wrap.warwick.ac.uk/id/eprint/30151

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