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endothelial cells as artery or vein have already been established. However, the
hypothesis that these endothelial cells possess flow-dependent phenotypic plas-
ticity has not been rigorously tested [ 13 , 14 ]. Although it has been long known that
venous grafts into the coronary artery (sometimes performed as a surgical
procedure for heart diseases) induce changes in the graft morphology such as
enlargement of grafted vessel diameter, the endothelial phenotypes are not thor-
oughly characterized at the molecular level.
3 Genetic Basis of Arterial and Venous Specification
(Specification by Chemical Signals)
As discussed in the previous sections, it has been long believed that arteriovenous
differentiation and maintenance of endothelial phenotypic identities are primarily
determined by the differential hemodynamic forces that they are exposed to.
However, more rigorous analyses are necessary to crystalize the hypothesis that
blood flow modulates the arteriovenous phenotypes of endothelial cells. In contrast,
the genetic basis of arteriovenous identity has been more rigorously studied, even
though this idea emerged within less than 15 years ago.
It all began when a single serendipitous finding was made in 1998 by Wang
et al [ 15 ]. They had been studying the role of the EphrinB2-EphB4 ligand-receptor
system in nervous system development. They generated EphrinB2-deficient mice
by introducing a lacZ reporter into the ephrinB2 gene locus (this mouse line is
referred to as EphrinB2: lacZ). This genetic manipulation system was commonly
used to disrupt a gene and at the same time it highlights the site(s) of expression of
the disrupted gene in vivo.
By investigating this mouse line, they found that EphrinB2 is expressed only in a
subset of the vascular system. Furthermore, the expression of a receptor for EphrinB2
ligand, EphB4, exhibited a perfect complimentary pattern to that of EphrinB2 in the
developing vascular system. Surprisingly, this complimentary expression pattern of
EphrinB2 and EphB4 was nearly the perfect mirror image of the arterial and venous
vascular system, respectively, that can be found in all histology and embryology
textbooks [ 15 ]. More surprisingly, it was discovered that the segregation of EphrinB2
and EphB4 expression to the arteries and veins, respectively, is established among
nearly all vascular beds prior to the initiation of blood circulation. This finding casts
doubt on the longstanding belief that blood circulation precedes the establishment of
arteriovenous specification, and provided hard evidence for the possibility that the
arteriovenous distinction is established prior to the onset of circulation. This single
discovery resulted in a major shift in our understanding of how arteriovenous
specification and patterning is established. This breakthrough finding was to
be followed by numerous investigations which culminated in our current view of
the genetic and molecular mechanisms underlying the differentiation and formation
of arteries and veins as discussed in the following sections.
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