Abstract
Exaggerated signaling by vascular endothelial growth factor (VEGF)‐A and its receptor, VEGFR2, in pathologies results in poor vessel function. Still, pharmacological suppression of VEGFA/VEGFR2 may aggravate disease. Delineating VEGFR2 signaling in vivo provides strategies for suppression of specific VEGFR2‐induced pathways. Three VEGFR2 tyrosine residues (Y949, Y1212, and Y1173) induce downstream signaling. Here, we show that knock‐in of phenylalanine to create VEGFR2 Y1212F in C57Bl/6 and FVB mouse strains leads to loss of growth factor receptor‐bound protein 2‐ and phosphoinositide 3′‐kinase (PI3K)p85 signaling. C57Bl/6 Vegfr2 Y1212F/Y1212F show reduced embryonic endothelial cell (EC) proliferation and partial lethality. FVB Vegfr2 Y1212F/Y1212F show reduced postnatal EC proliferation. Reduced EC proliferation in Vegfr2 Y1212F/Y1212F explants is rescued by c‐Myc overexpression. We conclude that VEGFR2 Y1212 signaling induces activation of extracellular‐signal‐regulated kinase (ERK)1/2 and Akt pathways required for c‐Myc‐dependent gene regulation, endothelial proliferation, and vessel stability.
Highlights
Vascular endothelial growth factor (VEGF)-A is a potent pro-angiogenic factor regulating endothelial cell (EC) proliferation, migration, vessel lumen formation, vessel pruning, and stability [1,2]
A point mutation was introduced in exon 27 of the Flk1 gene (Fig EV1A and B) to replace tyrosine 1212 with phenylalanine, creating Vegfr2Y1212F/Y1212F
We show here that the Y1212 phosphosite in VEGFR2 is critical for initiation of growth factor receptor-bound protein 2 (GRB2)/ERK1/2 and phosphoinositide 30-kinase (PI3K)/Akt pathways
Summary
Vascular endothelial growth factor (VEGF)-A is a potent pro-angiogenic factor regulating endothelial cell (EC) proliferation, migration, vessel lumen formation, vessel pruning, and stability [1,2]. VEGFA binds to VEGF receptor (VEGFR)-1 ( denoted Flt1) and VEGFR2 (denoted KDR in the human and Flk in the mouse) [3]. Binding of VEGFA to VEGFR2 leads to activation of the receptor tyrosine kinase and phosphorylation of tyrosines (Y) 949, 1052, 1057, 1173, and 1212 (mouse VEGFR2 sequence numbering) in the receptor intracellular domain [4]. Phosphorylated (p) Y949 in VEGFR2 mediates c-Src activation at EC junctions, and loss of pY949 signaling in Vegfr2Y949F/Y949F mice results in suppressed vascular leakage [4,5,6,7]. Vegfr2Y1173F/Y1173F mice die at embryonic day 8.5 (E8.5), due to suppressed EC differentiation, recapitulating the phenotype of the global Vegfr2/flk knockout mouse [15,16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
