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tal-stage and tissue-specific manner which is only poorly understood. It has
been postulated that non-hematopoietic EPOR expression results from the
common origin of various cell types; for example endothelial and hematopoi-
etic cells originate from the hemangioblast [96]. Based on this concept, the
finding of common anti-apoptotic, proliferative, differentiative, and angio-
genic effects of EPO in various tissues may be not surprising.
Vasculature
EPOR is expressed in human endothelial cells [97, 98]. By activation of
EPOR, EPO stimulates cell migration, proliferation, and differentiation of
endothelial cells into pro-angiogenic structures. It also stimulates endothelin
and matrix metalloproteinase (MMP-2) release, and an increase in cytosolic-
free calcium concentrations [97-102]. Studies on the in vitro and in vivo
effects of EPO on endothelial cells resulted in new concepts for using rEPO in
tissue regeneration or repair [8]. The affinity of EPOR to EPO is significantly
lower in endothelial cells (K d approximately 1 nM) than in erythroid cells (K d
approximately 50 pM) and may play a role in regulating the effects of EPO
[103, 104]. However, further investigations on the specific regulation of EPOR
expression on endothelial cells are necessary to understand how angiogenic
effects of EPO are regulated in health under chronic high EPO concentrations
(at high altitudes) or in disease (diabetes, artherosclerosis, or others).
EPO, expressed in bone marrow stroma cells, may also play a significant
paracrine role in bone marrow angiogenesis, particularly during development
[105-107]. EPOR is also expressed in (rat) smooth muscle cells [108, 109].
EPOR activation results in a direct vasopressive effect, suggesting that the
increase in blood pressure observed in some rEPO-treated patients may not be
only secondary to an increased blood volume. Recombinant EPO also nor-
malizes the contractile response of rat aortic sections in a state of shock. This
may be partly transmitted by ionic changes (Ca 2+ ) in smooth muscle cells after
rEPO administration [110]. Moreover, rEPO inhibits the activity of the
inducible nitric oxide synthase and reverts vascular dysfunction in a shock
model of splanchnic artery occlusion [111].
Musculature
EPOR expression is reported in primary murine satellite cells which are local-
ized at the basal lamina of adult skeletal muscle [112]. EPO increases the cyto-
plasmic calcium levels and enhances the proliferation of these cells, but
reduces differentiation and fusion into myotubes. Since satellite cells become
activated when a muscle is injured or diseased, EPO may participate in mus-
cle development or repair. Maturation to myotubes results in a down-regula-
tion of EPOR. EPOR are undetectable in mature myotubes or adult skeletal
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