VEGFR3 does not sustain retinal angiogenesis without VEGFR2

Abstract

Angiogenesis, the formation of new blood vessels, is regulated by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). VEGFR2 is abundant in the tip cells of angiogenic sprouts, where VEGF/VEGFR2 functions upstream of the delta-like ligand 4 (DLL4)/Notch signal transduction pathway. VEGFR3 is expressed in all endothelia and is indispensable for angiogenesis during early embryonic development. In adults, VEGFR3 is expressed in angiogenic blood vessels and some fenestrated endothelia. VEGFR3 is abundant in endothelial tip cells, where it activates Notch signaling, facilitating the conversion of tip cells to stalk cells during the stabilization of vascular branches. Subsequently, Notch activation suppresses VEGFR3 expression in a negative feedback loop. Here we used conditional deletions and a Notch pathway inhibitor to investigate the cross-talk between VEGFR2, VEGFR3, and Notch in vivo. We show that postnatal angiogenesis requires VEGFR2 signaling also in the absence of Notch or VEGFR3, and that even small amounts of VEGFR2 are able to sustain angiogenesis to some extent. We found that VEGFR2 is required independently of VEGFR3 for endothelial DLL4 up-regulation and angiogenic sprouting, and for VEGFR3 functions in angiogenesis. In contrast, VEGFR2 deletion had no effect, whereas VEGFR3 was essential for postnatal lymphangiogenesis, and even for lymphatic vessel maintenance in adult skin. Knowledge of these interactions and the signaling functions of VEGFRs in blood vessels and lymphatic vessels is essential for the therapeutic manipulation of the vascular system, especially when considering multitargeted antiangiogenic treatments.

The matricellular protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling

“…Of particular interest, increased Dll4 was observed in VEGF-R2-deficient mouse endothelium after Notch inhibition, suggesting that one or more additional factor(s) is or are involved (Zarkada et al, 2015). This is consistent with the independent action of CCN1 on the activation of Dll4/Notch signaling.…”

“…The same study emphasized a rather important role of VEGF-R3 in the regulation of sprouting of ECs with low Notch signaling activity. Another study by Zarkada et al demonstrated that genetic ablation of VEGF-R2 alone or in combination with VEGF-R3 prevented the increase of vascular density induced by Notch activation, suggesting that VEGF-R2 but not VEGF-R3 is required for the hypersprouting that occurred in the absence of Notch activation (Zarkada et al, 2015). In the same study, VEGF-R2 was required independently of VEGF-R3 for endothelial Dll4 upregulation and angiogenic sprouting, and for VEGF-R3 function in angiogenesis.…”

Molecular mechanism of inhibition of the abnormal proliferation of human umbilical vein endothelial cells by hydroxysafflor-yellow A

“…There are many studies on the biological function and intracellular signal transduction mechanism of VEGF and its receptors in tumour angiogenesis (Rivera & Bergers 2015), and the possibility of promoting some tumour metastasis (Yang et al 2015;Zarkada et al 2015). The biological activity of VEGF is mainly regulated by two tyrosine kinase receptors of VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1).…”

VEGF expression in pancreatic cancer and other malignancies: a review of the literature

“…In adults, VEGFR3 is expressed in angiogenic blood vessels and some fenestrated endothelia. VEGFR2 is required independently of VEGFR3 for endothelial DLL4 up-regulation and angiogenic sprouting, and for VEGFR3 functions in angiogenesis [21].…”