Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 177, Issue 1, Pages 481-492Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2010.090836
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Funding
- National Institutes of Health (NIH) [K08EY016139]
- Carl Marshall Reeves and Mildred Almen Reeves Foundation Inc
- Research to Prevent Blindness Inc
- International Retina Research Foundation
- American Federation for Aging
- American Retina Foundation
- IRRF Callahan Award
- NIH Vision Core [P30 EY 02687]
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Abnormal angiogenesis is central to the pathophysiology of diverse disease processes including cancers, ischemic and atherosclerotic heart disease, and visually debilitating eye disease. Resveratrol is a naturally occurring phytoalexin that has been demonstrated to ameliorate and decelerate the aging process as well as blunt end organ damage from obesity. These effects of resveratrol are largely mediated by members of the sirtuin family of proteins. We demonstrate that resveratrol can inhibit pathological angiogenesis in vivo and in vitro by a sirtuin-independent pathway. Resveratrol inhibits the proliferation and migration of vascular endothelial cells by activating eukaryotic elongation factor-2 kinase. The active kinase in turn phosphorylates and inactivates elongation factor-2, a key mediator of ribosomal transfer and protein translation. Functional inhibition of the kinase by gene deletion in vivo or RNA as well as pharmacological inhibition in vitro is able to completely reverse the effects of resveratrol on blood vessel growth. These studies have identified a novel and critical pathway that promotes aberrant vascular proliferation and one that is amenable to modulation by pharmacological means. In addition, these results have uncovered a sirtuin-independent pathway by which resveratrol regulates angiogenesis. (Am J Pathol 2010, 177:481-492; DOI: 10.2353/ajpath.2010.090836)
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