Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 613

Table 10.4. Molecules involved in arterial and venous differentiation of endothelial cells. Notch
targets 2 families of transcriptional repressors: hairy and enhancer of split (HES) and HES-
related (HRT) transcriptional regulators. Sonic Hedgehog and VEGF induce arterial cell fate.
Forkhead box-C transcription factors FoxC1 and FoxC2 control arterial specification via Delta-
like ligand DLL4, a Notch agonist. Nuclear receptor NR2f2 (a.k.a. chicken ovalbumin upstream
promoter transcription factor COUPTF2) suppresses the Notch pathway and inhibits neuropilin-1
expression. Ephrin-B2 and ephrin receptor EPHb4 are markers for arteries and veins, respectively.
Phosphatidylinositol 3-kinase inhibits the phospholipase-C 1-PKC-MAP2K-ERK pathway, an

effector of V EGF signaling for arterial fate. Protein kinase-B induces venous fate.

γ

Arterial fate Venous fate

VEGFa VEGFR3

Neuropilin-1 Neuropilin-2

Notch NR2f2

Ephrin-B2 EPHb4

Extracellular signal-regulated kinase Phosphatidylinositol 3-kinase

but it is also genetically programmed. Specific markers assigned to cells in each
compartment can be detected before the onset of circulation [ 1167 ].
Growth and specialization of arteries and veins continues throughout develop-
ment. Blood vessels adapt to experienced hemodynamic stresses. Arteriovenous
differentiation is controlled by hemodynamic factors. Blood vessels remodel ac-
cording to loading history. Concentric layers of vascular smooth myocytes and
elastic fibers ensure resistance to arteries. The venous low-pressure system is
provided with valves that open unidirectionally to prevent backflow.
Vasculature development depends on a combination of intrinsic prepatterning
and extrinsic responses to environmental parameters. The direction of moving blood
determines the differentiation in artery or vein, whether the lateral branch receives
blood or provides it. Arterial endothelial cells characterized by a spindle-like shape
in the streamwise direction have a low proliferation rate.
Some genes control the vascular specification into arteries and veins via sig-
naling molecules (Table 10.4 ). Arterial endothelial cells express certain transcription
factors, signaling molecules, gap-junction proteins, matrix molecules, and adhesion
proteins that are absent from veins.
The arteriovenous differentiation is done via different processes. Notch guides
arterial fate, as it targets Hairy and enhancer of Split (HES) and HES-related (HRT)
transcriptional regulators. In arteries, Notch signaling is indirectly stimulated by
VEGFa via VEGFR2 or neuropilin-1 and promoted by forkhead box transcription
factors FoxC1 and FoxC2 [ 1184 ]. One the other hand, Notch pathway in the venous
endothelium is suppressed by NR2f2 nuclear receptor. 14
Arterial expression profile is defined by marker ephrin-B2, whereas venous
pattern is identified by marker EPHb4 receptor. Neuropilin-1 is found in arteries,
whereas Nrp2 is restricted to veins and lymphatic vessels.

14 A.k.a. chicken ovalbumin upstream promoter transcription factor COUPTF2).