Mechanical and Chemical Regulation of Arterial and Venous Specification - Mechanical and Chemical Signaling in Angiogenesis - page 8

3.2 VEGF Signaling in Arterial Vessel Specification
In 2002, discoveries by three independent studies unveiled a surprising mechanism
underlying arterial specification. In studying a transgenic mouse line where VEGF-
A was over expressed in the heart, it was found that nearly all cardiac endothelial
cells become EphrinB2 + , indicating that VEGF-A can transdifferentiate venous
endothelial cells (EphB4 + ) to arterial type (EphrinB2 + )[ 34 ]. Interestingly, this
VEGF-mediated arterial transdifferentiation was found to be inhibited by angio-
poietin-1 [ 34 ]. Another angiopoietin, angiopoietin-2, also inhibited this arterial
transdifferentiation, but this inhibition caused the endothelial cells to assume
EphrinB2 - /EphB4 - phenotype indicating that they are neither arterial nor venous
types [ 34 ].
In another study, cultured endothelial cells can be induced to express EphrinB2
upon treatment with VEGF-A164 [ 35 ]. In this study, it was further shown that
arteries, but not veins, specifically align with peripheral sensory neurons, and
VEGF-A164 is expressed by these neurons and Schwann cells [ 35 ]. In the mutant
mice where peripheral neurons or Schwann cells are eliminated, arteriogenesis is
disrupted. However, in the mutant with disorganized neurons, arteries remain
aligned with misrouted neurons. Another report by the same group has shown that
the deficiency of VEGF-A expression in sensory neurons, motor neurons or
Schwann cells results in the elimination of arterial marker expression, while the
alignment of the vessels with sensory neurons remained intact [ 36 ]. In this study, it
was further reported that the arterial differentiation is mediated by endothelial
expression of Nrp1 (an artery-specific VEGF co-receptor) which is induced by
VEGF derived from peripheral sensory neurons and Schwann cells [ 36 ]. These
results indicate that peripheral nerve derived VEGF induce arterial specification
via Nrp1 mediated positive-feedback.
In a third study, it was reported that VEGF-A is expressed by somite of
developing zebrafish embryo in notochords-derived Shh-dependent manner [ 37 ].
In this report, it was also shown that loss of VEGF or Shh results in failure of
arterial specification [ 37 ]. Furthermore, it was shown that exogenous overex-
pression of VEGF or Shh causes ectopic expression of arterial markers. Expression
of VEGF in the embryos lacking Shh signaling rescues the defects in arterial
differentiation [ 37 ]. These results indicate that notochord-derived Shh promotes
VEGF expression by somite, which induces arterial specification.
Based on these three independent studies, two major conclusions can be drawn.
VEGF-A is a major inducer of arterial endothelial specification during develop-
ment. Furthermore, these studies indicate an unexpected plasticity of an endo-
thelial phenotype: Venous endothelial cells can be converted to arterial type by
VEGF-A.