A Ligand-Independent VEGFR2 Signaling Pathway Limits Angiogenic Responses in Diabetes

Abstract

Although vascular complications are a hallmark of diabetes, the molecular mechanisms that underlie endothelial dysfunction are unclear. We showed that reactive oxygen species generated from hyperglycemia promoted ligand-independent phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2). This VEGFR2 signaling occurred within the Golgi compartment and resulted in progressively decreased availability of VEGFR2 at the cell surface. Consequently, the responses of endothelial cells to exogenous VEGF in a mouse model of diabetes were impaired because of a specific deficiency of VEGFR2 at the cell surface, despite a lack of change in transcript abundance. Hyperglycemia-induced phosphorylation of VEGFR2 did not require intrinsic receptor kinase activity, and was instead mediated by Src family kinases. The reduced cell surface abundance of VEGFR2 in diabetic mice was reversed by treatment with the antioxidant N-acetyl-L-cysteine, suggesting a causative role for oxidative stress. These findings uncover a mode of ligand-independent VEGFR2 signaling that can progressively lead to continuously muted responses to exogenous VEGF and limit angiogenic events.

Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) as a therapeutic target to prevent retinal vasopermeability during diabetes

“…In agreement to others (31), we also found that LPC transactivated VEGFR2, and that this transactivation, which did not require VEGF, was a key signaling pathway in the induction of LPC-induced permeability both in vitro and in vivo. Transactivation of VEGFR2 may thus occur within the cell, possibly through reactive oxygen species (32). Taken together, our data lend further support to the central role of VEGFR2 and its kinase activity in VEGF-dependent and independent vascular permeability.…”

Aspectos celulares y moleculares de la nefropatía diabética, rol del VEGF-A

“…El SRA, el VEGF-A y la nefrinuria fueron implicados en este proceso [18][19][20]22,[33][34][35][36][37][38] . Los podocitos y las células endoteliales en cultivo incrementaron la expresión de VEGF-A y de VEGFR2 en respuesta al aumento de glucosa [39][40][41] .…”

“…Warren y col. demostraron que en la diabetes la hiperglucemia disminuye la actividad del VEGFR2 endotelial 41 . La generación de ROS causada por la hiperglucemia, indujo activación del VEGFR2 y su posterior degradación, independientemente del VEGF-A 41 .…”

Principles of Redox Signaling

“…In keeping with this, ROS generated from hyperglycemia promoted ligand-independent phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2). Hyperglycemia-induced phosphorylation of VEGFR2 did not require intrinsic receptor kinase activity and was instead mediated by Src family kinases [ 210 ].…”