Abstract
Vascular development is regulated by complicated signals and molecules in vertebrates. In this study, we characterized a novel function of carboxypeptidase N1 (Cpn1) in the vasculature. We show that cpn1 mRNA is expressed in developing vessels. The knockdown of cpn1 by morpholino injection impairs the growth of intersegmental vessels (ISV) and caudal vein plexus (CVP), suggesting the role of cpn1 in vascular development. We showed that vascular defects are not caused by cell death but are due to the impairment of migration and proliferation. Consistent with vascular growth defects, loss of cpn1 affects the expression of the vascular markers flt4, mrc1, flk, stabilin, and ephrinb2. Furthermore, the overexpression of cpn1 impaired the growth of ISV and CVP, but the remodeling expression of vascular markers was different from the knockdown of cpn1, indicating the differential regulation mechanisms in cpn1-overexpressing embryos. We examine the interaction between cpn1 and multiple signals and observed that cpn1 is regulated by Notch/VEGF signals for ISV growth and likely regulates BMP signals for CVP patterning. In conclusion, we demonstrate that cpn1 has a critical role in the vascular development of zebrafish. We also reveal a fine-tune regulation of cpn1 that controls vascular patterning mediated by multiple signals.
Highlights
The development of vertebrate embryos depends on a precisely patterned, integrated network of blood vessels that supply oxygen and nutrients
Despite growing knowledge of the pathways leading to artery specification and intersegmental vessels (ISV) growth, little is known about the molecular mechanisms leading to vein specification, tip–stalk cell specification, and caudal vein plexus (CVP) patterning
Current evidence suggests that VEGFC/VEGFR3 signaling is essential for vein identity and ISV tip cell identity mediated by VEGFA/VEGFR2 signal and inactivation of Notch signal[13, 14], and BMP signaling is involved in CVP formation[15,16,17]
Summary
The development of vertebrate embryos depends on a precisely patterned, integrated network of blood vessels that supply oxygen and nutrients. After the formation of arteries and veins, angioblasts undergo further proliferation and migration to form a patterned network of small vessels, such as the growth of the trunk intersegmental vessels (ISVs) and caudal vein plexus (CVP) in zebrafish, which makes it ideal for investigating angiogenesis[8]. As the vessels migrate, leading tip cells take an active role in sensing the environment for guidance cues, whereas nonmigratory stalk cells lumenize and lose filopodia[10,11,12] In addition to their embryonic role in angiogenesis, tip cells are involved in new vessel growth in many diseases. Cpn[1] overexpression caused vascular defects, suggesting the role of cpn[1] in controlling the growth of ISV and CVP. We explore the regulation of cpn[1] mediated by VEGF and Notch signals to control ISV growth and observe that cpn[1] contributes to CVP formation through interaction with BMP signals
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