VEGF Secreted by Hypoxic Muller Cells Induces MMP-2 Expression and Activity in Endothelial Cells to Promote Retinal Neovascularization in Proliferative Diabetic Retinopathy

被引：109

作者：

Rodrigues, Murilo ^{[1
]}

Xin, Xiaoban ^{[1
]}

Jee, Kathleen ^{[1
]}

Babapoor-Farrokhran, Savalan ^{[1
]}

Kashiwabuchi, Fabiana ^{[1
]}

Ma, Tao ^{[2
,3
,4
]}

Bhutto, Imran ^{[1
]}

Hassan, Syed Junaid ^{[1
]}

Daoud, Yassine ^{[1
]}

Baranano, David ^{[1
]}

Solomon, Sharon ^{[1
]}

Lutty, Gerard ^{[1
]}

Semenza, Gregg L. ^{[5
,6
,7
,8
,9
,10
,11
]}

Montaner, Silvia ^{[2
,3
,4
]}

Sodhi, Akrit ^{[1
]}

机构：

[1] Johns Hopkins Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA

[2] Univ Maryland, Sch Dent, Dept Oncol & Diagnost Sci, Baltimore, MD 21201 USA

[3] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA

[4] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA

[5] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Vasc Program, Baltimore, MD USA

[6] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA

[9] Johns Hopkins Univ, Sch Med, Dept Radiat Oncol, Baltimore, MD USA

[10] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA

[11] Johns Hopkins Univ, Sch Med, Dept Med Genet, Baltimore, MD USA

来源：

DIABETES | 2013年 / 62卷 / 11期

基金：

美国国家卫生研究院;

关键词：

TYPE-1; MATRIX-METALLOPROTEINASE; ANGIOGENESIS; ACTIVATION; INHIBITORS; MATRIX-METALLOPROTEINASE-9; VASCULATURE; GELATINASE; MEMBRANES; TIMP-2; MICE;

D O I：

10.2337/db13-0014

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-1 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.

引用

页码：3863 / 3873

页数：11

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