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2.4. Effects of cytokines on EPC
2.4.1 Vascular endothelial growth factor
Since the VEGF-receptor KDR was used for the primary identification of
EPC, an effect of VEGF on EPC was to be expected. Therefore,
Asahara
et al. (1999b)
studied the effects of VEGF on mobilization and migration
of EPC. VEGF
165
was shown to have a mobilizing effect on EPC and
the total MNC fraction. Furthermore, a migration of EPC toward VEGF
was also documented. EPC homing relies on the creation of a gradient of
endogenous proteins. One of the best studied is VEGF, a homodimeric
glycoprotein with a molecular weight of 45 kDa that is synthesized by nor-
mal cells and upregulated by hypoxia. VEGF is not only secreted locally
where it has paracrine-like effects but also secreted into circulation and acts
as a hormone (
Asahara et al., 1999b
). In the presence of hypoxia, transcrip-
tion factors like hypoxia-inducible factor-1a (HIF-1a) are activated, leading
to increased levels of VEGF (
Nakamura et al., 2004
). VEGF leads then
through a cascade of mechanisms to a migration of EPC and hematopoietic
cells (
Dery et al., 2005
).
The migratory effects of VEGF on EPC have been described several
times, whereas a correlation between systemic VEGF levels and EPC mobi-
lization has been described differently (
Groger et al., 2010; Langenberg et al.,
2010a; Piatkowski et al., 2009; Spring et al., 2005
).
2.4.2 SDF-1
CXCL12 or stromal-cell-derived factor-1a (SDF-1a) is a chemokine that has
been identified to be crucial for EPC mobilization in a HIF-1a-dependent
manner (
Ceradini et al., 2004
) and also recruitment along hypoxic gradients
via the CXCR4 receptor (
Yamaguchi et al., 2003
). During tumor growth or
hypoxia, SDF-1a is secreted (
Fang and Salven, 2011; Foresta et al., 2011;
Peichev et al., 2000; Schuh et al., 2008; Yamaguchi et al., 2003
). Formation
of the SDF-1a gradient leads to mobilization of EPC. But this effect of EPC
mobilization by SDF-1a seems to be in a paracrine fashion. Therefore, ele-
vated levels of SDF-1a can be found in ischemic tissues and in the BM
(
Morris et al., 2010; Pitchford et al., 2009
). Some studies have even shown
that other cytokines have a stronger effect on EPC than SDF-1a (
Grieb et al.,
2012; Leone et al., 2006b
), for example, in acute myocardial infarction
(AMI) patients, SDF-1a was elevated but not as strong as granulocyte-
colony stimulating factor (G-CSF;
Leone et al., 2006b
), and the effect of
Macrophage Migration Inhibitory factor
(MIF) on EPC is
stronger
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