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- Title
VEGF Secreted by Hypoxic Müller Cells Induces MMP-2 Expression and Activity in Endothelial Cells to Promote Retinal Neovascularization in Proliferative Diabetic Retinopathy.
- Authors
Rodrigues, Murilo; Xiaoban Xin; Jee, Kathleen; Babapoor-Farrokhran, Savalan; Kashiwabuchi, Fabiana; Tao Ma; Bhutto, Imran; Hassan, Syed Junaid; Daoud, Yassine; Baranano, David; Solomon, Sharon; Lutty, Gerard; Semenza, Gregg L.; Montaner, Silvia; Sodhi, Akrit
- Abstract
In proliferative diabetic retinopathy (PDR), retinal ischemia promotes neovascularization (NV), which can lead to profound vision loss in diabetic patients. Treatment for PDR, panretinal photocoagulation, is inherently destructive and has significant visual consequences. Therapies targeting vascular endothelial growth factor (VEGF) have transformed the treatment of diabetic eye disease but have proven inadequate for treating NV, prompting exploration for additional therapeutic options for PDR patients. In this regard, extracellular proteolysis is an early and sustained activity strictly required for NV. Extracellular proteolysis in NV is facilitated by the dysregulated activity of matrix metalloprotein-ases (MMPs). Here, we set out to better understand the regulation of MMPs by ischemia in PDR. We demonstrate that accumulation of hypoxia-inducible factor-1α in Müller cells induces the expression of VEGF, which, in turn, promotes increased MMP-2 expression and activity in neighboring endothelial cells (ECs). MMP-2 expression was detected in ECs in retinal NV tissue from PDR patients, whereas MMP-2 protein levels were elevated in the aqueous of PDR patients compared with controls. Our findings demonstrate a complex interplay among hypoxic Müller cells, secreted angiogenic factors, and neighboring ECs in the regulation of MMP-2 in retinal NV and identify MMP-2 as a target for the treatment of PDR.
- Subjects
DIABETIC retinopathy; VASCULAR endothelial growth factors; DIABETES; LIGHT coagulation; ENDOTHELIAL cells
- Publication
Diabetes, 2013, Vol 62, Issue 11, p3863
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db13-0014