The hematopoietic growth factor erythropoietin (Epo) circulates in plasma and controls the oxygen carrying capacity of the
blood (Fisher. Exp Biol Med (Maywood) 228:1–14, 2003). Epo is produced primarily in the adult kidney and fetal liver and was
originally believed to play a role restricted to stimulation of early erythroid precursor proliferation, inhibition of apoptosis,
and differentiation of the erythroid lineage. Early studies showed that mice with targeted deletion of Epo or the Epo receptor
(EpoR) show impaired erythropoiesis, lack mature erythrocytes, and die in utero around embryonic day 13.5 (Wu et al. Cell
83:59–67, 1995; Lin et al. Genes Dev. 10:154–164, 1996). These animals also exhibited heart defects, abnormal vascular development
as well as increased apoptosis in the brain suggesting additional functions for Epo signaling in normal development of the
central nervous system and heart. Now, in addition to its well-known role in erythropoiesis, a diverse array of cells have
been identified that produce Epo and/or express the Epo-R including endothelial cells, smooth muscle cells, and cells of the
central nervous system (Masuda et al. J Biol Chem. 269:19488–19493, 1994; Marti et al. Eur J Neurosci. 8:666–676, 1996; Bernaudin
et al. J Cereb Blood Flow Metab. 19:643–651, 1999; Li et al. Neurochem Res. 32:2132–2141, 2007). Endogenously produced Epo
and/or expression of the EpoR gives rise to autocrine and paracrine signaling in different organs particularly during hypoxia,
toxicity, and injury conditions. Epo has been shown to regulate a variety of cell functions such as calcium flux (Korbel et
al. J Comp Physiol B. 174:121–128, 2004) neurotransmitter synthesis and cell survival (Velly et al. Pharmacol Ther. 128:445–459,
2010; Vogel et al. Blood. 102:2278–2284, 2003). Furthermore Epo has neurotrophic effects (Grimm et al. Nat Med. 8:718–724,
2002; Junk et al. Proc Natl Acad Sci U S A. 99:10659–10664, 2002), can induce an angiogenic phenotype in cultured endothelial
cells and is a potent angiogenic factor in vivo (Ribatti et al. Eur J Clin Invest. 33:891–896, 2003) and might enhance ventilation
in hypoxic conditions (Soliz et al. J Physiol. 568:559–571, 2005; Soliz et al. J Physiol. 583, 329–336, 2007). Thus multiple
functions have been identified breathing new life and exciting possibilities into what is really an old growth factor.
This review will address the function of Epo in non-hematopoietic tissues with significant emphasis on the brain and heart.