Nervy Vasculature

Abstract

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 32, No. 7Nervy Vasculature Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBNervy Vasculature Victoria M. Bedell and Stephen C. Ekker Victoria M. BedellVictoria M. Bedell From the Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN. Search for more papers by this author and Stephen C. EkkerStephen C. Ekker From the Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN. Search for more papers by this author Originally published1 Jul 2012https://doi.org/10.1161/ATVBAHA.112.251272Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32:1546–1547Blood vessel formation is a critical process during development and in response to normal wound healing. Precocious vasculature formation is associated with a variety of diseases such as cancer. The zebrafish (Danio rerio) has become a powerful model system to illuminate the molecular mechanisms underlying vasculogenesis. Some inherent advantages of the zebrafish include the following: external development that does not require vessel neogenesis for embryo formation, transparent embryos and larva, ready panel of transgenics that use fluorescent proteins for noninvasive imaging, and a full molecular genetic toolbox.See accompanying article on page 1563Recent work has shown that the evolutionary origin of many vascular factors is tied to their biochemical history in nervous system formation.1,2 One mechanism for the deployment of neural patterning genes in blood vessel formation is genome duplication followed by hijacking for use.1,2 In the study by Rissone et al, the authors show a role for more neural players in blood vessel formation, β-neurexin (β-NRXN1a), and neuroligin (NLGN1). NRXNs are cell adhesion molecules that play a role in synaptic activity, whereas NLGNs interact with NRXNs in synapse biology.3–5 The role of NLGNs in vessel formation has not been previously studied.Rissone et al focused on the vascular structure called the caudal plexus (CP). In fish embryos, this region undergoes angiogenesis with subsequent anastomosis and later remodeling.6,7 The present article carefully documents this progression through embryonic development and defines β-NRXN1a and NLGN1 expression in the CP during normal development. In β-NRXN1a knockdown animals, vascular remodeling fails, with a dramatic looping phenotype observed in the blood vessels.Using the strength of their model organism, the authors used morpholino oligonucleotides to coknockdown several known angiogenic genes to look for genetic interactions. Specifically, the authors explore the connection between NRXN signaling and the extracellular matrix (ECM). Prior work demonstrates that ECM interacting forms of vascular endothelial growth factor A are critical for vessel formation in mammals.8–12 In zebrafish, the ECM-modifying enzyme HS6ST-2 is also critical for CP formation and vascular branching.13 Rissone et al show that β-NRXN1a and NLGN1 genetically interact with vascular endothelial growth factor A, and their noted loss-of-function phenotypes are similar to the loss of HS6ST-2.13 Together, these results implicate the ECM as a critical component in β-NRXN1a and NLGN signaling during vascular formation.Rissone et al14 use the ability of the zebrafish to readily knockdown multiple genes to study interactions that would be difficult in other model organisms. Furthermore, they begin to define how the endothelial cells work together with the ECM to correctly pattern new blood vessels and remodel existing vessels.With this data, we can now think about how the CP can be used as a new model for precocious vascular formation, such as cancer vessels. Because tumor vasculature is a combination of angiogenesis and remodeling (see Nagy et al15 for review), the CP could be an excellent way to study normal vascular remodeling within a time frame that makes gene manipulation relatively simple. Does NRXN/NLGN signaling participate in the progression of cancer or other blood vessel–based disease?The evolutionary relationship between critical components of nervous system and vascular development is intriguing. However, most of the data to date have been finding neural patterning genes play a role in vascular development. Is it possible that the evolution goes both ways? For example, is the role of the ECM, as seen in vascular development, a mechanism that also plays a role in neural plasticity?DisclosuresNone.FootnotesCorrespondence to Stephen C. Ekker, Mayo Clinic, 200 1st St SW, 1342C Guggenheim, Rochester, MN 55905. E-mail [email protected]