Journal
DEVELOPMENT
Volume 143, Issue 20, Pages 3796-3805Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.137919
Keywords
ERK; Vegfa; Angiogenesis; Artery differentiation; Zebrafish
Categories
Funding
- National Heart, Lung, and Blood Institute (NHLBI) [R01HL093467, R01HL122599]
- Uehara Memorial Foundation
- Japan Society for the Promotion of Science (JSPS)
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Vascular endothelial growth factor a (Vegfa) is essential for blood vessel formation and can induce activation of numerous signaling effectors in endothelial cells. However, it is unclear how and where these function in developmental contexts during vascular morphogenesis. To address this issue, we have visualized activation of presumptive Vegfa effectors at single-cell resolution in zebrafish blood vessels. From these studies, we find that phosphorylation of the serine/threonine kinase ERK (pERK) preferentially occurs in endothelial cells undergoing angiogenesis, but not in committed arterial endothelial cells. pERK in endothelial cells was ectopically induced by Vegfa and lost in Vegfa signaling mutants. Both chemical and endothelial autonomous inhibition of ERK prevented endothelial sprouting, but did not prevent initial artery differentiation. Timed chemical inhibition during angiogenesis caused a loss of genes implicated in coordinating tip/stalk cell behaviors, including flt4 and, at later stages, dll4. ERK inhibition also blocked excessive angiogenesis and ectopic flt4 expression in Notch-deficient blood vessels. Together, these studies implicate ERK as a specific effector of Vegfa signaling in the induction of angiogenic genes during sprouting.
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