Mechanical and Chemical Regulation of Arterial and Venous Specification - Mechanical and Chemical Signaling in Angiogenesis - page 10

specification [ 42 , 43 ]. Therefore, further studies are necessary to delineate the
exact role of PI3K/Akt in arterial cell fate determination.
3.4 Forkhead Box (Fox) Transcription Factors in Arterial
Specification
Two family members of the Foxc subclass of Fox transcription factors, Foxc1 and
Foxc2, are indicated for their role in arterial specification [ 44 , 45 ]. Targeted dis-
ruption of Foxc1 and Foxc2 in mice results in arteriovenous malformation which is
accompanied by aberrant expression of several arterial markers such as Dll4 and
Notch1. It is also reported that there are Foxc-binding sites in the upstream pro-
moter region of the Dll4 gene, supporting the idea that Foxc transcription factors
activate the Dll4 gene which induces Notch signaling, a primary signaling pathway
that is required for arterial specification.
3.5 Venous Identity and Coup-TFII
It had been believed that venous identify of endothelial cells is a default state of
these cells and arterial fate is an acquired state by the activation of Notch signaling
[ 46 ]. However, it was later reported that the venous state of endothelial differ-
entiation requires the suppression of Notch signaling by a transcription factor,
COUP-TFII (chicken ovalbumin upstream promoter-transcription factor II) [ 47 ].
COUP-TFII is a member of the orphan nuclear receptor superfamily and is spe-
cifically expressed in venous, but not in arterial, endothelial cells [ 47 , 48 ].
Conditional ablation of the COUP-TFII gene in endothelial cells in mice results in
the acquisition of an arterial phenotype in veins manifested by the expression of
arterial markers, such as EphrinB2, Npr1, and Notch-signaling molecules [ 47 ].
Furthermore, these mutant veins that acquired arterial marker expression are able
to form haematopoietic cell clusters and recruit smooth-muscle cells, two func-
tional features of normal arteries [ 47 ]. These results indicate that COUP-TFII
deficient venous endothelial cells not only acquire arterial markers, but also
function as arteries.
In addition, it was shown that ectopic expression of COUP-TFII in endothelial
cells in mice results in an abnormal fusion of arteries and veins, a phenotype that is
a mirror image of Npr1 or Notch1 mutant mice [ 47 ]. In this study, it was also
shown that the ectopic expression of COUP-TFII leads to a loss of expression of
arterial markers, including Nrp1 and the Notch signaling molecules. All of these
results are in support of the idea that COUP-TFII expression in veins suppresses
the Notch signaling, thus leading to the maintenance of the venous phenotype of
endothelium.