Soluble forms of VEGF receptor-1 and -2 promote vascular maturation via mural cell recruitment.
Two soluble forms of vascular endothelial growth factor (VEGF) receptors, sVEGFR-1 and sVEGFR-2, are physiologically released and overproduced in some pathologies. They are known to act as anti-VEGF agents. Here we report that these soluble receptors contribute to vessel maturation by mediating a dialogue between endothelial cells (ECs) and mural cells that leads to blood vessel stabilization. Through a multidisciplinary approach, we provide evidence that these soluble VEGF receptors promote mural cell migration through a paracrine mechanism involving interplay in ECs between VEGF/VEGFR-2 and sphingosine-1-phosphate type-1 (S1P)/S1P1 pathways that leads to endothelial nitric oxyde synthase (eNOS) activation. This new paradigm is supported by the finding that sVEGFR-1 and -2 perform the following actions: 1) induce an eNOS-dependent outgrowth of a mural cell network in an ex vivo model of angiogenesis, 2) increase the mural cell coverage of neovessels in vitro and in vivo, 3) promote mural cell migration toward ECs, and 4) stimulate endothelial S1P1 overproduction and eNOS activation that promote the migration and the recruitment of neighboring mural cells. These findings provide new insights into mechanisms regulating physiological and pathological angiogenesis and vessel stabilization.
Lorquet
Sophie
S
University of Liège, Laboratory of Tumor and Developmental Biology, GIGA-Cancer, Institute of Pathology, CHU-B23, B-4000 Liège, Belgium.
Berndt
Sarah
S
Blacher
Silvia
S
Gengoux
Emily
E
Peulen
Olivier
O
Maquoi
Erik
E
Noël
Agnès
A
Foidart
Jean-Michel
JM
Munaut
Carine
C
Péqueux
Christel
C
D000818:Animals; D001483:Base Sequence; D001808:Blood Vessels / Q000254:growth & development*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D017931:DNA Primers; D006801:Humans; D051379:Mice; D012995:Solubility; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*
D017077:Culture Media, Conditioned; D017931:DNA Primers; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2