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Despite the clear major contribution of hyperlipidemia to the prevalence of cardiovascular disease in the developed world, the direct effects of lipoproteins on endothelial cells have remained obscure and are under debate. Here we report a previously uncharacterized mechanism of vessel growth modulation by lipoprotein availability. Using a genetic screen for vascular defects in zebrafish, we initially identified a mutation, stalactite (stl), in the gene encoding microsomal triglyceride transfer protein (mtp), which is involved in the biosynthesis of apolipoprotein B (ApoB)-containing lipoproteins. By manipulating lipoprotein concentrations in zebrafish, we found that ApoB negatively regulates angiogenesis and that it is the ApoB protein particle, rather than lipid moieties within ApoB-containing lipoproteins, that is primarily responsible for this effect. Mechanistically, we identified downregulation of vascular endothelial growth factor receptor 1 (VEGFR1), which acts as a decoy receptor for VEGF, as a key mediator of the endothelial response to lipoproteins, and we observed VEGFR1 downregulation in hyperlipidemic mice. These findings may open new avenues for the treatment of lipoprotein-related vascular disorders.

The zebrafish has proven to be a powerful model organism for studying how the stereotypic and evolutionarily conserved vascular network is established during vertebrate development. The combination of genetic and experimental tools with high‐resolution imaging has allowed rapid progress in our understanding of both the cellular and molecular mechanisms underlying the specification of endothelial progenitors as well as the differentiation and patterning of blood vessels into arterial‐venous networks. Continued studies of vascular development in zebrafish promise to yield new insights into the developmental mechanisms regulating lymphangiogenesis and will undoubtedly reveal new information about the role of the endothelium in the patterning of various tissues. In this chapter, we discuss recent advances in vascular biology that have been achieved through use of the zebrafish.