Mechanical and Chemical Regulation of Arterial and Venous Specification - Mechanical and Chemical Signaling in Angiogenesis - page 11

3.6 Other Signaling Pathways Involved in Arterial Vessel
Specification

In addition to the above discussed chemical factors that contribute to arteriovenous
specification, there are several other chemical factors that are somewhat less
characterized for their roles in this process.
The G protein-coupled receptor APJ is preferentially expressed in venous
endothelial cells [ 49 , 50 ]. Morpholino knockdown of APJ and its ligand, Apelin, in
Xenopus results in defects in intersomitic vessel development [ 51 ]. However, no
obvious vascular defects are detectable in APJ null mice [ 52 ].
Members of the Sry-related HMG box (Sox) family of transcription factors
have also been indicated for their roles in arteriovenous differentiation [ 53 - 55 ].
It has been reported that Sox7 and Sox18 are both expressed in developing
vasculature and their double knockdown results in arteriovenous malformation.
A member of the sucrose non fermenting kinase family (snrk-1) has been
implicated to act downstream of or in parallel to Notch signaling and function
upstream of grl [ 56 ]. Calcitonin receptor like receptor (crlr) expressed by devel-
oping somites is a receptor for adrenomedullin and suggested to be under the
regulation of shh and to control arterial differentiation as an upstream regulator of
VEGF [ 57 ]. However, the exact roles of these factors in controlling arteriovenous
differentiation remains unknown.

4 Integrated Mechanisms Underlying Arteriovenous
Specification by Chemical Signals

As discussed above, in less than the last 15 years, extraordinary advances have
been made in our understanding of the detailed molecular basis of the arterial and
venous specification (Fig. 3 ). It seems clear that activation of Notch signaling is
the central pathway in arterial specification. This signaling is activated by multiple
inputs such as those that lead to the activation of VEGF, Foxc1/2, and Plc-c/PKC/
MEK/ERK signals. Ectopic activation of any of these signals in venous endothelial
cells can override the genetic program determining their phenotype, and they
acquire

the arterial phenotype. This plasticity of arterial-venous phenotypes

persists even in adult endothelial cells.
In contrast, the mechanism underlying venous specification is less understood.
Activation of a transcription factor, COUP-TFII, in venous endothelial cells is
required for retaining their phenotype. It is also reported that the activation of
PI3K/Akt signaling is involved in venous specification, even though its site of
action remains unclear. Although COUP-TFII and PI3K/Akt signaling are
involved in venous specification, their primary function appears to be the sup-
pression of arterial phenotype, rather than the induction of an venous phenotype.
Furthermore,

rendering a venous phenotype in arterial endothelial cells by