Abstract
SummarySprouting blood vessels are led by filopodia-studded endothelial tip cells that respond to angiogenic signals. Mosaic lineage tracing previously revealed that NRP1 is essential for tip cell function, although its mechanistic role in tip cells remains poorly defined. Here, we show that NRP1 is dispensable for genetic tip cell identity. Instead, we find that NRP1 is essential to form the filopodial bursts that distinguish tip cells morphologically from neighboring stalk cells, because it enables the extracellular matrix (ECM)-induced activation of CDC42, a key regulator of filopodia formation. Accordingly, NRP1 knockdown and pharmacological CDC42 inhibition similarly impaired filopodia formation in vitro and in developing zebrafish in vivo. During mouse retinal angiogenesis, CDC42 inhibition impaired tip cell and vascular network formation, causing defects that resembled those due to loss of ECM-induced, but not VEGF-induced, NRP1 signaling. We conclude that NRP1 enables ECM-induced filopodia formation for tip cell function during sprouting angiogenesis.
Highlights
Developing organs, ischemic tissues, and growing tumors produce the vascular endothelial growth factor VEGF-A to signal to its receptors on the endothelial cells (ECs) that line all blood vessels, and the resulting angiogenic expansion of local vasculature ensures the delivery of oxygen and nutrients to sustain fundamental metabolic processes (Potente et al, 2011)
Neuropilin 1 (NRP1) Promotes Vessel Ingression into and Branching within the Neural Parenchyma Using the mouse embryo hindbrain as a model for angiogenesis (Fantin et al, 2013b), we have recently shown that NRP1 confers a selective advantage to ECs competing for the tip cell position in growing vessel sprouts (Fantin et al, 2013a)
Immunohistochemistry for the vascular endothelial marker platelet endothelial cell adhesion molecule (PECAM) showed that vessel ingression was mildly delayed in hindbrains carrying one, and severely delayed in hindbrains carrying two, Nrp1 null alleles (Figures 1A–1C)
Summary
Developing organs, ischemic tissues, and growing tumors produce the vascular endothelial growth factor VEGF-A to signal to its receptors on the endothelial cells (ECs) that line all blood vessels, and the resulting angiogenic expansion of local vasculature ensures the delivery of oxygen and nutrients to sustain fundamental metabolic processes (Potente et al, 2011). The resulting early embryonic lethality of these mutants has precluded investigations into the role of CDC42 in filopodia formation, tip cell function, and sprouting angiogenesis in vivo. It is not known if VEGF-A and/or ECM cues are important for CDC42 regulation during vessel sprouting
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