Physiological and molecular erythropoietic responses to hypoxia

Hypoxia is an essential physiological element and a main feature of all pathophysiological states. While severe hypoxia is used in research, moderate is typical for many physiological and pathological states. Despite this, our understanding of moderate hypoxia is limited. One of the defining outcomes of hypoxia is a subsequent increase in erythropoiesis. While erythropoietin (EPO) is considered the master regulator of erythropoiesis, additional roles in cytoprotection, embryogenesis, and inotropy have recently emerged. The kidney is considered the primary source of EPO in health and pathology, however multiple tissues are capable of expression. These sources have largely been uninvestigated and are considered physiologically irrelevant in health. The aims of this thesis were to address our limited understanding of the pathophysiology of moderate hypoxia and determine the physiological significance of extrarenal sources of EPO. We hypothesize that (1) severe and moderate hypoxia will invoke opposing cardiovascular responses and (2) extrarenal EPO is required for hematopoiesis and cardiogenesis. Exposure to 24 hours of either moderate or severe hypoxia resulted in hypotension and hypertension, respectively, following normoxic recovery. This was mediated by heterogeneous autonomic activation, despite similar vasodilatory responses via up-regulation of heme oxygenase-1. Subsequently, the molecular response to moderate and severe hypoxia was compared via whole-body analysis of EPO expression. Critically, we identified that the brain was the sole responder to moderate hypoxia. To further our understanding of extrarenal EPO expression, we investigated the physiological significance of cardiac-derived EPO. We showed that cardiac EPO expression is a complex interplay of multiple cell types that is differentially expressed throughout life. Generation of cardiomyocyte-specific EPO knockout mice resulted in increased cardiac EPO expression suggesting over-compensation from another cardiac cell type. This resulted in both systemic and cardiac-specific effects in adult animals. These findings expand our knowledge of hypoxia to include responses at moderate levels. We propose that there is neither a primary site of EPO nor a singular effect. Rather, our data indicates that EPO is expressed by multiple tissues in a time and pathology dependent manner. Further, tissue EPO production is not always for hematopoiesis but is required for both paracrine and endocrine functions.