Biomedical Engineering Reference
In-Depth Information
10.6.1.4
Slit Ligands and Roundabout Receptors
Slit ligands (Slit1-Slit3) are involved in neuronal and vascular development. They
bind to Roundabout receptors (Robo1-Robo4) that belong to the immunoglobulin
superfamily of transmembrane signaling molecules. The Slit-Robo signaling in-
duces repulsion. Slits are involved in heart morphogenesis, angiogenesis, and tumor
metastasis.
Vascular endothelium-specific Roundabout-4 has an extracellular domain dif-
ferent from that of all other Robo family members. Receptor Robo4 activated by
Slit2 maintains vasculature integrity [
892
]. Stabilizing factor Robo4 is expressed
in developing blood vessels where it can neutralize VEGF, but it is not required
for developmental angiogenesis. During sprouting, Robo4 is only expressed by
more mature, stabilized endothelial cells that form sprout stems. The Robo4-Slit2
signaling counteracts hyperpermeability induced by VEGF that uses Src and Yes
kinases. In addition, activated Robo4 impedes endothelial cell migration primed by
fibroblast growth factor-2 [
1219
]. Angiogenic endothelial cells (as well as many
other cell types) also express Robo1 receptor. Because Slit2 binding to Robo1
promotes angiogenesis, Slit2 positively and negatively regulates angiogenesis by
binding to Robo1 and Robo4, respectively.
10.6.2
Transcriptional Regulators
10.6.2.1
Hairy and Enhancer of Split-Related Transcription Factors
Two genes — Hrt1 and Hrt2 — that encode Hairy enhancer of Split (HES)-related
transcriptional regulators (HRT) are major contributors of vessel formation [
1220
].
The combined loss of transcription factors HRT1 and HRT2 does not influence
initial vasculogenesis, but it does affect subsequent development of major vessels.
10.6.2.2
Homeobox Transcription Factors
Homeobox (Hox) gene-encoded transcriptional factors are temporally and spatially
restricted regulators of tissue patterning during embryogenesis owing to their DNA-
binding homeodomain. The Hox regulators are involved in cell differentiation,
proliferation, and migration. In particular they participate in endothelial cell fate,
especially the transcriptional control of genes responsible for angiogenesis and
vascular remodeling. The Hox transcription factors regulate genes involved in
cell- and cell-matrix interactions, such as the expression of
α
V
β
3
-integrin, matrix
metallopeptidase MMP14, or urokinase plasminogen activator receptor [
1221
].
These proteins contribute to matrix remodeling during angiogenesis. The HOX
genes are characterized by their clustered genomic arrangement. Each HOX gene
can have up to 3 paralogs within independent clusters.
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