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Originally published online as doi:10.2353/ajpath.2010.081152 on November 30, 2009

Published online before print November 30, 2009
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(American Journal of Pathology. 2010;176:504-515.)
© 2010 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2010.081152

Endothelial Progenitor Cells (EPCs) Mobilized and Activated by Neurotrophic Factors May Contribute to Pathologic Neovascularization in Diabetic Retinopathy

Xialin Liu*, Yongjun Li{dagger}, Yizhi Liu*, Yan Luo*, Dingding Wang*, Brian H. Annex{ddagger} and Pascal J. Goldschmidt-Clermont§

From the Zhongshan Ophthalmic Center,* State Key Laboratory of Ophthalmology, Sun Yat-Sen University, Guangzhou, China; the Department of Vascular Surgery,{dagger} Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; the Department of Medicine,{ddagger} University of Virginia, Charlottesville, Virginia; and the University of Miami Leonard M. Miller School of Medicine,§ Miami, Florida

Diabetic retinopathy is characterized by pathological retinal neovascularization. Accumulating evidence has indicated that high levels of circulating endothelial progenitor cells (EPCs) are an important risk factor for neovascularization. Paradoxically, the reduction and dysfunction of circulating EPCs has been extensively reported in diabetic patients. We hypothesized that EPCs are differentially altered in the various vasculopathic complications of diabetes mellitus, exhibiting distinct behaviors in terms of angiogenic response to ischemia and growth factors and potentially playing a potent role in motivating vascular precursors to induce pathological neovascularization. Circulating levels of EPCs from diabetic retinopathy patients were analyzed by flow cytometry and by counting EPC colony-forming units, and serum levels of neurotrophic factors were measured by enzyme-linked immunosorbent assay. We found increased levels of nerve growth factor and brain-derived neurotrophic factor in the blood of diabetic retinopathy patients; this increase was correlated with the levels of circulating EPCs. In addition, we demonstrated that retinal cells released neurotrophic factors under hypoxic conditions to enhance EPC activity in vitro and to increase angiogenesis in a mouse ischemic hindlimb model. These results suggest that neurotrophic factors may induce neoangiogenesis through EPC activation, leading to the pathological retinal neovascularization. Thus, we propose that neovascularization in the ischemic retina might be regulated by overexpression of neurotrophic factors.






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