The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching

Abstract

Blood vessel formation requires the integrated regulation of endothelial cell proliferation and branching morphogenesis, but how this coordinated regulation is achieved is not well understood. Flt-1 (vascular endothelial growth factor [VEGF] receptor 1) is a high affinity VEGF-A receptor whose loss leads to vessel overgrowth and dysmorphogenesis. We examined the ability of Flt-1 isoform transgenes to rescue the vascular development of embryonic stem cell–derived flt-1−/− mutant vessels. Endothelial proliferation was equivalently rescued by both soluble (sFlt-1) and membrane-tethered (mFlt-1) isoforms, but only sFlt-1 rescued vessel branching. Flk-1 Tyr-1173 phosphorylation was increased in flt-1−/− mutant vessels and partially rescued by the Flt-1 isoform transgenes. sFlt-1–rescued vessels exhibited more heterogeneous levels of pFlk than did mFlt-1–rescued vessels, and reporter gene expression from the flt-1 locus was also heterogeneous in developing vessels. Our data support a model whereby sFlt-1 protein is more efficient than mFlt-1 at amplifying initial expression differences, and these amplified differences set up local discontinuities in VEGF-A ligand availability that are important for proper vessel branching.

Regulation of Angiogenesis by Histone Chaperone HIRA-mediated Incorporation of Lysine 56-acetylated Histone H3.3 at Chromatin Domains of Endothelial Genes

“…VEGFR1 expression is up-regulated in blood vessels that are growing and being remodeled (6,7). Gene targeting studies demonstrated that VEGFR1 Ϫ/Ϫ mice die in utero between days 8.5 and 9.0 (6) because of a lack of organized vasculature.…”

Activation of the VEGFR1 Chromatin Domain

“…Activation of VEGFR1 by VEGF induces migration of endothelial cells lacking VEGFR2 (7). Recent studies showed that VEGFR1 loss is associated with decreased vascular sprout formation, migration, and vascular branching (8,9). This phenotype was also observed in vivo, as VEGFR1 Ϫ/Ϫ embryos had defective sprouting from the dorsal aorta (9).…”

“…Recent studies showed that VEGFR1 loss is associated with decreased vascular sprout formation, migration, and vascular branching (8,9). This phenotype was also observed in vivo, as VEGFR1 Ϫ/Ϫ embryos had defective sprouting from the dorsal aorta (9). Consequently, signaling through VEGFR1 positively modulates endothelial cell migration and vascular branching.…”

Placental growth factor neutralising antibodies give limited anti-angiogenic effects in an in vitro organotypic angiogenesis model

“…Although the levels of VEGFR-1 appear to be lower than of VEGFR-2 whether this a real quantitative difference, or reflects the quality of the antibodies used is not clear. Soluble VEGFR-1 (sVEGFR-1) is thought to play a role in regulating tube formation in certain experimental systems [22]. sVEGFR-1 was expressed at significant levels (3,647 ± 1,931 pg/ml), confirming VEGFR-1 is present in both the membrane localised form and the soluble form.…”

“…In development VEGFR-1 appears to act as a decoy receptor, which together with PlGF, is suggested to regulate local free levels of VEGF-A and hence VEGFR signalling [22]. However, in the adult the function is different.…”