Both EPO and EPO-R are ubiquitously distributed in neural tissues [Digicaylioglu 1995]. Except larger vessels, EPO-R is abundantly distributed in astrocytes, neurons, and cerebral capillary endothelia [Marti 1996, Yamaji 1996, Bernaudin 1999, Brines 2000]. Immunohistochemistry shows that these distributions of EPO-R are consistent with the anatomical location of blood-brain barrier (BBB) [Brines 2000]. Such a condensed distribution of EPO-R within and surrounding the cerebral capillaries implies that a small amount of EPO is sufficient to mediate physiological function in the central nervous system [Chin 2000]. The increased production of EPO in response to hypoxia and anemia by astrocytes and neurons corresponds to that which occurs in kidney and liver [Masuda 1994]. Thus, during hypoxia, EPO acts directly on cerebral capillary endothelial cells as an angiogenic factor through a paracrine mechanism from the astrocytes and an endocrine mechanism from the kidney [Digicaylioglu 1995].