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to improve blood supply to injured organs by acting on endothe-
lial progenitor cells (EPCs; Fig.
2
, pathway 5) (
196
). CD34+/
Flk-1 (also known KDR or VEGFR2) positive cells are hematopoi-
etic progenitor cells that may differentiate into endothelial cells
and contribute to neovascularization and vascular repair (
197,
198
). Epo promotes proliferation (
40, 196
), inhibits apoptosis
(
199
), and facilitates differentiation of EPCs (
200-203
).
Furthermore, Epo induces mobilization of EPCs into the circula-
tion (
204, 205
), and their homing (
155, 206, 207
). Increased
eNOS expression and BH4 biosynthesis has been shown in Epo-
treated EPCs and vascular cells (Fig.
2
; pathway 4) (
205, 208
).
Interestingly, recent studies on hypoxic endothelial cells have
shown that VEGFR2 can also become an additional component for
the EpoR/bCR complex that is essential for NO production
(reviewed by ref.
75
). Similar to other non-hematopoietic cells
PI3K/Akt signaling cascades, induction of mitogen-activated pro-
tein kinase (MEK)/extracellular signal regulated kinase (ERK)
signaling pathways (
83, 147
) and NO production are known to
mediate Epo effects in endothelial cells in animal models and
humans patients (see Figs.
1
and
2
, pathway 1).
Thus indeed augmented endothelial function may play a major
role in Epo-mediated protection in non-hematopoietic cells and
underlie a significant amount of tissue recovery from injury.
Certainly more research needs to be carried out regarding this pos-
sibility and the consequences for the future use of Epo as a treat-
ment strategy.
9
Risks Associated with Epo Therapy
Although Epo is considered a clinically safe-to-use drug (due to its
long term use by anemic patients), a number of worrying risks have
been associated with its more general use as a therapeutic. The
frequent use of Epo mimetics in patients with chronic kidney dis-
ease (CKD) has recently declined as randomized trials demon-
strated increased incidence of cardiovascular complications and
mortality without a marked benefit in quality of life (reviewed by
ref.
209
). Safety concerns were raised during treatment of anemia
in diabetic patients with CKD when they showed a twofold higher
risk of stroke, an increased risk of venous thromboembolism and
cancer-related deaths (
210
). Several studies have suggested that
exposure to high doses of Epo mimetics, when needed to achieve
higher hemoglobin levels, is harmful and explains this phenome-
non (
211, 212
). Very high doses of Epo, in conjunction with
hypoxia, have also been associated with a paradoxical neurotoxic
effect suggesting dose-response conditions need to be optimized.
In the clinics there are also considerable concerns about potential
thrombotic complications. Recent trials in which very high doses
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