1. VEGF secreted by hypoxic Muller cells induces MMP-2 expression and activity in endothelial cells to promote retinal neovascularization in proliferative diabetic retinopathy
- Author
-
Rodrigues, Murilo, Xin, Xiaoban, Jee, Kathleen, Babapoor-Farrokhran, Savalan, Kashiwabuchi, Fabiana, Ma, Tao, Bhutto, Imran, Hassan, Syed Junaid, Daoud, Yassine, Baranano, David, Solomon, Sharon, Lutty, Gerard, Semenza, Gregg L., Montaner, Silvia, and Sodhi, Akrit
- Subjects
Diabetic retinopathy -- Development and progression -- Genetic aspects -- Research ,Neovascularization -- Physiological aspects -- Genetic aspects -- Research ,Vascular endothelial growth factor -- Physiological aspects -- Genetic aspects -- Research ,Health - 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 metalloproteinases (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 Muller 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 Muller 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. Diabetes 62:3863-3873, 2013, Diabetic retinopathy (DR) is the most common microvascular complication in the diabetic population. Development of DR is directly related to the duration of diabetes; 20 years after diagnosis, nearly all [...]
- Published
- 2013
- Full Text
- View/download PDF