Biology Reference
In-Depth Information
muscle. The presence of rEPO increases EPOR expression levels six-fold in
murine myblasts (C2C12 cells) [112]. The associated two-fold up-regulation
of GATA-3 expression levels by rEPO may mediate changes in the cellular
proliferation and differentiation. GATA-3 may also limit EPO gene expression
by binding on the EPO promoter as a negative regulatory element [113].
Heart
In fetal mice, EPOR is expressed in the heart in a temporal and cell type-spe-
cific manner. EPOR is initially detectable at day 10.5 of gestation, and its
expression persists until day 14.5. During this period, EPOR expression is
found in the endocardium (endothelial cells), epicardium (mesothelial cells),
and pericardium, but not in the myocardium [16]. Evidence for the biologic rel-
evance of EPO in the heart is given by the finding of ventricular hypoplasia
coupled to defects in the intraventricular septum both in EPO
-/-
and EPOR
-/-
mice. These animals die at day 13.5 of gestation and also suffer from detach-
ment of the epicardium and abnormalities in the vascular network.
Immunohistochemistry indicates EPOR expression in the mycocardium at
embryonic day 11.5 (E11.5) [114]. Although EPOR expression could not be
detected at E13.5 by
in situ
hybridization, a reduced cell number is the most
consistent and significant finding at this stage of development [16]. Lack of
EPOR does not affect the initial commitment of cells to cardiomyocyte devel-
opment, but the number of proliferating cells is markedly reduced in EPO
-/-
and
EPOR
-/-
mutant fetal mice. Accordingly, rEPO significantly stimulates the pro-
liferation of fetal murine cardiomyocytes
in vitro
. Furthermore, chimeric analy-
sis provides evidence that EPO triggers murine cardiomyocyte proliferation in
a non-cell-autonomous manner [16]. Therefore, it has been postulated that acti-
vation of EPOR in the endo- or epicardium is required for the initiation of a cas-
cade of events leading to the secretion of a mitogenic factor in the myocardium.
Such interactions are essential for other factors involved in normal cardiac
development. Cardiac defects in EPO
-/-
and EPOR
-/-
mutant fetal mice result
in suppressed cardiac function with fetal hydrops and appear to be independent
of the general state of hypoxia due to the lack of onset in “definitive”
hematopoiesis [16]. EPOR deficiency increases apoptosis in the endocardium
and myocardium, which may be primarily and/or secondarily caused [114].
In humans, Juul et al. reported only weak EPOR immunoreactivity in the
fetal myocardium at five weeks
post conceptionem
, but increasing EPOR stain-
ing by eight and 18 weeks pc [115]. In endothelial cells derived from human
adult myocardial tissue (cardiac auricle), rEPO has a significant angiogenic
potential which is equal to that of vascular endothelial growth factor (VEGF)
[116]. These data suggest that EPO not only has a role in normal cardiac devel-
opment, but also acts as an angiogenic and anti-apoptotic factor on endothelial
cells in the heart, which makes it an agent with potential in myocardial repair in
ischemic heart disease or in inflammatory processes of the epi- or endocardium.
