Abstract
Advanced glycation end products (AGEs), produced by the non-enzymatic glycation of proteins and lipids under hyperglycemia or oxidative stress conditions, has been implicated to be pivotal in the development of diabetic vascular complications, including diabetic retinopathy. We previously demonstrated that Src kinase played a causative role in AGE-induced hyper-permeability and barrier dysfunction in human umbilical vein endothelial cells (HUVECs). While the increase of vascular permeability is the early event of angiogenesis, the effect of Src in AGE-induced angiogenesis and the mechanism has not been completely revealed. Here, we investigated the impact of Src on AGE-induced HUVECs proliferation, migration, and tubulogenesis. Inhibition of Src with inhibitor PP2 or siRNA decreased AGE-induced migration and tubulogenesis of HUVECs. The inactivation of Src with pcDNA3/flag-SrcK298M also restrained AGE-induced HUVECs proliferation, migration, and tube formation, while the activation of Src with pcDNA3/flag-SrcY530F enhanced HUVECs angiogenesis alone and exacerbated AGE-induced angiogenesis. AGE-enhanced HUVECs angiogenesis in vitro was accompanied with the phosphorylation of ERK in HUVECs. The inhibition of ERK with its inhibitor PD98059 decreased AGE-induced HUVECs angiogenesis. Furthermore, the inhibition and silencing of Src suppressed the AGE-induced ERK activation. And the silencing of AGEs receptor (RAGE) inhibited the AGE-induced ERK activation and angiogenesis as well. In conclusions, this study demonstrated that Src plays a pivotal role in AGE-promoted HUVECs angiogenesis by phosphorylating ERK, and very likely through RAGE-Src-ERK pathway.
Highlights
As one of the microvascular complications of diabetes, proliferative diabetic retinopathy (PDR) poses a threat to the vision of patients with diabetes (You et al, 2013)
Human umbilical vein endothelial cells were incubated with 100 μg/mL advanced glycation end products (AGEs) for 24 h to explore the effects of AGEs on endothelial proliferation, migration, and tube formation
Compared to the control group, human umbilical vein endothelial cells (HUVECs) proliferation was significantly enhanced by the treatment of AGEs (P < 0.05) (Figure 1A)
Summary
As one of the microvascular complications of diabetes, proliferative diabetic retinopathy (PDR) poses a threat to the vision of patients with diabetes (You et al, 2013). The pathological process mainly involves the apoptosis of pericytes, the disruption of blood retinal barrier, the increase of vascular permeability, the thickening of capillary basement membrane, and the pathological angiogenesis (Patz, 1982; Frank, 2004; Park et al, 2014). Angiogenesis is the process of forming new capillaries mainly involving the coordinated control of the permeability of microvessels, the migration, proliferation, polarity, and differentiation of endothelial cells, the deposition of basement membrane, and the formation and maturation of tubules (Herbert and Stainier, 2011). Excessive angiogenesis is a critical pathological process in the development of macular edema as well as PDR. Substantial success has been achieved by targeting angiogenesis in cancer and eye diseases
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