The cardiovascular system is the first organ to form during embryogenesis and is critical for the survival and subsequent development of the embryo. Vascular development is defined as two processes, vasculogenesis and angiogenesis. Vasculogenesis is the process of differentiation and assembly of endothelial cells into primitive vessels. Subsequently, angiogenesis is responsible for the remodeling and expansion of the premature vascular plexus into a highly organized complex network. The fact that the basic blueprint for outgrowth of the vascular tree is evolutionarily conserved indicates that vascular guidance is controlled genetically. Vascular guidance is dependent upon directional sprouting, involving proliferation, migration and tube formation of endothelial cells that are the basic unit of a vessel. Nerves often share common paths with blood vessels throughout the entire organism. Neuronal patterning is mainly mediated by four major pathways: Netrins, Semaphorins, Ephrins, and Slits, interacting with their cognate families of receptors. Recent efforts have demonstrated that molecular mechanisms initiated by Ephrins and Semaphorins for guiding neuronal patterning also regulate endothelial sprouting and angiogenesis. In order to identify additional vascular guidance mechanisms, two parallel strategies were undertaken. First, I hypothesized that putative guidance genes could be identified by examining mutants in which the normal routes of sprouting blood vessels are disrupted. With this strategy I was able to identify a novel Robo homologue, Robo4, based on its differential expression in an Alk-1 targeted mouse. Our data suggest that Robo4 is a vascular-specific Robo receptor that plays a role in angiogenesis and vascular patterning, analogous to the roles played by other Robo receptors in patterning axons in the nervous system. Second, because of recent evidence for shared guidance mechanisms between the nervous and vascular systems, candidate gene approaches were also performed to screen for vascular expression of known neuronal guidance genes. This approach led to the identification of Unc5h2, one of the Netrin receptors in the nervous system, as a putative vascular guidance protein. Our data indicate that Netrin promotes angiogenesis in vitro and in vivo. This suggests that Netrin-Unc5h2 signaling is also involved in angiogenesis in addition to its roles in neuronal guidance. I generated an Unc5h2 conditional allele and mice are currently being bred and will be characterized to elucidate the in vivo roles of netrin-Unc5h2 signaling in vascular development. Together, these experimental data, and those of others, strongly indicate that the four major pathways that regulate axonal guidance have been adapted by the vascular system for its patterning. These shared guidance cues are likely responsible for generating the superimposable patterns of and functional cooperation between the neuronal and vascular systems.
University of Utah;
Genetics; Molecular Mechanisms;
Cardiovascular System; Neurons; Growth and Development;
University of Utah;
Relation-Is Version Of
Digital reproduction of “Slit and Netrin are vascular guidance factors”. Spencer S. Eccles Health Sciences Library. Print version of “Slit and Netrin are vascular guidance factors”. available at J. Willard Marriott Library Special Collection, QP6.5 2004 .P36.