Abstract
Vessel growth integrates diverse extrinsic signals with intrinsic signaling cascades to coordinate cell migration and sprouting morphogenesis. The pro-angiogenic effects of Vascular Endothelial Growth Factor (VEGF) are carefully controlled during sprouting to generate an efficiently patterned vascular network. We identify crosstalk between VEGF signaling and that of the secreted ligand Semaphorin 3fb (Sema3fb), one of two zebrafish paralogs of mammalian Sema3F. The sema3fb gene is expressed by endothelial cells in actively sprouting vessels. Loss of sema3fb results in abnormally wide and stunted intersegmental vessel artery sprouts. Although the sprouts initiate at the correct developmental time, they have a reduced migration speed. These sprouts have persistent filopodia and abnormally spaced nuclei suggesting dysregulated control of actin assembly. sema3fb mutants show simultaneously higher expression of pro-angiogenic (VEGF receptor 2 (vegfr2) and delta-like 4 (dll4)) and anti-angiogenic (soluble VEGF receptor 1 (svegfr1)/ soluble Fms Related Receptor Tyrosine Kinase 1 (sflt1)) pathway components. We show increased phospho-ERK staining in migrating angioblasts, consistent with enhanced Vegf activity. Reducing Vegfr2 kinase activity in sema3fb mutants rescues angiogenic sprouting. Our data suggest that Sema3fb plays a critical role in promoting endothelial sprouting through modulating the VEGF signaling pathway, acting as an autocrine cue that modulates intrinsic growth factor signaling.
Highlights
Sprouting angiogenesis is a process by which new vessels branch and grow from existing vessels, establishing the perfusion of tissues and organs
Semaphorin 3fb is both produced by, and acts on the precursors of blood vessels as they migrate, a process known as autocrine control
We find that losing Semaphorin 3fb leads to stalled blood vessel growth, indicating it normally acts as a positive signal
Summary
Sprouting angiogenesis is a process by which new vessels branch and grow from existing vessels, establishing the perfusion of tissues and organs. Vessel growth is highly dependent on Vascular Endothelial Growth Factor (VEGF) signaling, which functions as a master regulator to promote angiogenesis, and is often dysregulated in disease [1,2,3,4]. VEGF gradients within tissues are responsible for the initial triggering and guidance of the sprouting process signaling through the endothelial-expressed tyrosine kinase VEGF receptor 2 (VEGFR2) [5,6,7], activating downstream signaling including that of the MAPK-ERK pathway. Dll positive cells activate the Notch receptor in stalk cells [14,15,16] to down-regulate VEGF receptor expression and limit the response of the stalk cell to environmental VEGF [17,18,19]
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