TY - JOUR
T1 - PEDF is an endogenous inhibitor of VEGF-R2 angiogenesis signaling in endothelial cells
AU - Zhang, Mingliang
AU - Tombran-Tink, Joyce
AU - Yang, Songyang
AU - Zhang, Xiaomin
AU - Li, Xiaorong
AU - Barnstable, Colin J.
N1 - Funding Information:
This work was supported by National Natural Science Foundation of China (CN) ( 81900894 , 81870675 , 81870651 ); the Natural Science Foundation of Tianjin ( 18JCQNJC11300 ); the Tianjin Key Clinical Discipline (Specialty) Project ( TJLCZDXKQ004 ); the Independent and open project of Tianjin Key Laboratory of retinal function and disease( 2019tjswmm004 ); and by The Macula Vision Research Foundation , the David Woods Kemper Memorial Foundation.
Funding Information:
This work was supported by National Natural Science Foundation of China (CN) (81900894,81870675,81870651); the Natural Science Foundation of Tianjin (18JCQNJC11300); the Tianjin Key Clinical Discipline (Specialty) Project (TJLCZDXKQ004); the Independent and open project of Tianjin Key Laboratory of retinal function and disease(2019tjswmm004); and by The Macula Vision Research Foundation, the David Woods Kemper Memorial Foundation.
Publisher Copyright:
© 2021
PY - 2021/12
Y1 - 2021/12
N2 - Pigment epithelium derived factor (PEDF), an endogenous inhibitor of angiogenesis, targets the growth of aberrant blood vessels in many tissues, including the eye. In this study we show that PEDF prevented early mitogenic signals of vascular endothelial growth factor (VEGF-A) in primate retinal endothelial cells, blocking proliferation, migration and tube formation. PEDF inhibited the phosphorylation and activation of five major downstream VEGF-A signaling partners, namely phosphoinositide-3-OH Kinase (PI3K), AKT, FAK, Src (Y416), and PLC-γ. It did so by binding to the extracellular domain of VEGF-R2, blocking VEGF-A-induced tyrosine phosphorylation (Tyr 951 and Tyr 1175), and inhibiting VEGF-R2 receptor kinase activity. PEDF had no effect on the transcription or translation of VEGF-R2 in cultured HUVECs. PEDF also bound to the extracellular domain of VEGF-R1. We conclude that PEDF blocks the growth of new blood vessels, in part, by reducing VEGF-A activation of its key mitogenic receptor, VEGF-R2, and by preventing its downstream signals in endothelial cells.
AB - Pigment epithelium derived factor (PEDF), an endogenous inhibitor of angiogenesis, targets the growth of aberrant blood vessels in many tissues, including the eye. In this study we show that PEDF prevented early mitogenic signals of vascular endothelial growth factor (VEGF-A) in primate retinal endothelial cells, blocking proliferation, migration and tube formation. PEDF inhibited the phosphorylation and activation of five major downstream VEGF-A signaling partners, namely phosphoinositide-3-OH Kinase (PI3K), AKT, FAK, Src (Y416), and PLC-γ. It did so by binding to the extracellular domain of VEGF-R2, blocking VEGF-A-induced tyrosine phosphorylation (Tyr 951 and Tyr 1175), and inhibiting VEGF-R2 receptor kinase activity. PEDF had no effect on the transcription or translation of VEGF-R2 in cultured HUVECs. PEDF also bound to the extracellular domain of VEGF-R1. We conclude that PEDF blocks the growth of new blood vessels, in part, by reducing VEGF-A activation of its key mitogenic receptor, VEGF-R2, and by preventing its downstream signals in endothelial cells.
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U2 - 10.1016/j.exer.2021.108828
DO - 10.1016/j.exer.2021.108828
M3 - Article
C2 - 34742690
AN - SCOPUS:85118558192
SN - 0014-4835
VL - 213
JO - Experimental Eye Research
JF - Experimental Eye Research
M1 - 108828
ER -