Abstract
Genetic regulators and signaling pathways are important for the formation of blood vessels. Transcription factors controlling vein identity, intersegmental vessels (ISV) growth and caudal vein plexus (CVP) formation in zebrafish are little understood as yet. Here, we show the importance of the nuclear receptor subfamily member 1A (nr2f1a) in zebrafish vascular development. Amino acid sequence alignment and phylogenetic analysis of nr2f1a is highly conserved among the vertebrates. Our in situ hybridization results showed nr2f1a mRNA is expressed in the lateral plate mesoderm at 18 somite stage and in vessels at 24–30 hpf, suggesting its roles in vasculization. Consistent with this morpholino-based knockdown of nr2fla impaired ISV growth and failed to develop fenestrated vascular structure in CVP, suggesting that nr2f1a has important roles in controlling ISV and CVP growth. Consequently, nr2f1a morphants showed pericardial edema and circulation defects. We further demonstrated reduced ISV cells and decreased CVP endothelial cells sprouting in nr2f1a morphants, indicating the growth impairment of ISV and CVP is due to a decrease of cell proliferation and migration, but not results from cell death in endothelial cells after morpholino knockdown. To test molecular mechanisms and signals that are associated with nr2f1a, we examined the expression of vascular markers. We found that a loss of nr2f1a results in a decreased expression of vein/ISV specific markers, flt4, mrc1, vascular markers stabilin and ephrinb2. This indicates the regulatory role of nr2f1a in controlling vascular development. We further showed that nr2f1a likely interact with Notch signaling by examining nr2f1a expression in rbpsuh morphants and DAPT-treatment embryos. Together, we show nr2f1a plays a critical role for vascular development in zebrafish.
Highlights
Vertebrate blood vessels are critical for nutrient and oxygen supply and are developed in an evolutionarily conserved manner
Pereira et al showed that mammalian Nr2f2 (CoupTFII) is required for angiogenesis and heart development mediated by downregulating a proangiogenic soluble factor angiopoietin-1 [11]
In the present study we examined the role of nr2f1a in angiogenesis in vivo during zebrafish development
Summary
Vertebrate blood vessels are critical for nutrient and oxygen supply and are developed in an evolutionarily conserved manner. After the establishment of these vessels, additional vessels develop from pre-existing vessels by angiogenesis This process includes sprouting, migration, lumenization, branching and fusion to form a coordinated pattern of the vessel plexus, which is tightly controlled by growth factors, regulators and multiple signaling pathways. The dorsal aorta (DA) and posterior cardinal vein (PCV) form a primitive circulatory loop during vasculogenesis, sprouting angiogenesis from the DA to form intersegmental vessels (ISVs) and from the axial vein to develop a honeycomb-like network called caudal vein plexus (CVP) via distinct signalling pathways. These are proliferative and show multiple filopodia, while the less proliferative, stationary cells which lumenize behind the tip cell are called stalk cells [7] This process is largely controlled by VEGF and Notch signalling. Wiley and co-workers showed recently that BMP signalling pathways regulate sprouting angiogenesis
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