Abstract
Notch is a critical regulator of angiogenesis and arterial specification. We show that ectopic expression of activated Notch1 induces endothelial morphogenesis in human umbilical vein endothelial cells (HUVEC) in a VEGFR-1-dependent manner. Notch1-mediated upregulation of VEGFR-1 in HUVEC increased their responsiveness to the VEGFR-1 specific ligand, Placental Growth Factor (PlGF). In mice and human endothelial cells, inhibition of Notch signaling resulted in decreased VEGFR-1 expression during VEGF-A-induced neovascularization. In summary, we show that Notch1 plays a role in endothelial cells by regulating VEGFR-1, a function that may be important for physiological and pathological angiogenesis.
Highlights
Vascular endothelial growth factor-A (VEGF-A) is essential to the multistep process of vascular development, and proper vessel formation in a variety of settings is exquisitely sensitive to levels of VEGF-A [ 1– 4]
Because human umbilical vein endothelial cells (HUVEC) were cultured in the presence of multiple growth factors, we determined if this effect was due to signaling through a particular receptor using specific small molecule inhibitors for fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and VEGFR
Notch signaling is known to down-regulate VEGFR-2 expression, we hypothesized that the Notch-induced extensions were mediated by VEGFR-1 [ 20, 29]
Summary
Vascular endothelial growth factor-A (VEGF-A) is essential to the multistep process of vascular development, and proper vessel formation in a variety of settings is exquisitely sensitive to levels of VEGF-A [ 1– 4]. VEGF-A signals through two receptor tyrosine kinases: VEGFR-1 (flt1) and VEGFR-2 (flk1), while placenta growth factor (PlGF) signals exclusively through VEGFR-1 Both VEGF-A and PlGF induce endothelial cell proliferation, survival, and migration [ 3, 5, 6]. VEGFR-1 is thought to function mainly as a decoy receptor that sequesters VEGF-A [ 7– 11] This concept is supported by analysis of mouse models where deletion of flt[1] led to vessel overgrowth and disruption of vascular patterning [ 12]. Mice expressing a mutant allele of flt[1] that lacks the tyrosine kinase domain ( flt1TK -/- ) did not exhibit the vascular patterning defects seen in flt1-/- mice, suggesting that in embryonic development, the kinase activity of VEGFR-1 was dispensable and that its predominant function is via its high affinity binding to VEGF-A [ 9]. The signaling pathways that regulate VEGFR-1 expression in endothelial cells remain unclear
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