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

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 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.

HIF-1α acts as a molecular target for simvastatin cytotoxicity in B16.F10 melanoma cells cultured under chemically induced hypoxia

“…3 and 4, respectively. As previously reported (6,10), the present study confirmed that the addition of 200 µM CoCl 2 to melanoma cells increased the expression level of HIF-1α by 68% compared with its level in the same cells cultured under normoxia (P<0.05).…”

“…In addition, the expression of MIG, an angiostatic protein (37), was suppressed by 60% upon hypoxic induction of HIF-1α production. However, probably as a compensatory mechanism for this effect, the levels of the anti-angiogenic proteins PF-4, TIMP-2 and IL-12p70 were also increased in cells treated with CoCl 2 (10).…”

“…To mimic hypoxia, B16.F10 melanoma cells were cultured in the presence of cobalt chloride (CoCl 2 ), a chemical inducer of HIF-1α stabilization (9,10). The mechanisms of cytotoxicity exerted by SIM on B16.F10 cells grown in the presence of the CoCl 2 were investigated with regard to tumor cell production of HIF-1α and expression of proteins involved in main tumorigenic processes coordinated by this protein, including angiogenesis and inflammation (11,12).…”

MiR-886-5p Inhibition Inhibits Growth and Induces Apoptosis of MCF7 Cells

“…Thus, expression levels of these MMPs effectively reflect the DOI:http://dx.doi.org/10.7314/APJCP.2014.15.4.1511 Inhibitor Inhibits Growth and Induces Apoptosis of MCF7 Cells aggressiveness of tumor cells and are associated with poor prognosis in various cancers. Such MMPs include MMP2 and MMP9, which are pivotal in degrading the basement membrane and have been proven to facilitate tumor invasion and metastasis in many types of cancer cells (Rodrigues et al, 2013). In this study, we found that miR-886-5p inhibitor could inhibit the expression of MT1-MMP, MMP2, and MMP9.…”

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

“…34 Collectively, these changes lead to upregulation of angiogenic molecules VEGF-A, erythropoietin (EPO), and other vascular growth factors [34][35][36][37] and result in pathologic angiogenesis, increased vascular leakage, and bleeding. [38][39][40] Diabetes-induced dysfunctional cerebral neovascularization response is vastly different from the neovascularization observed in other vascular beds. In the coronary circulation, diabetes alters the balance between pro-and antiangiogenic growth factors, impairs endothelial function, and mediates an imbalance in microenvironment redox state of the coronary circulation 41 resulting in impaired coronary collateral growth and cardiac angiogenesis.…”