Cellular and molecular defenses against hypoxia

Abstract

The ability to cope with hypoxia is essential for the development and survival of all vertebrate species. Cellular hypoxia occurs when oxygen demand exceeds oxygen supply. The development of cellular hypoxia depends both on the type of tissue and partial pressure oxygen (PO2) in the tissue, because cells can vary extremely in their physiologic oxygen demand. Under normal conditions up to 90 % of the available oxygen is consumed by mitochondria to yield ATP through oxidative phosphorylation. Thus, oxygen deprivation will always lead to fundamental changes in cell metabolism and function. Different physiological systems have evolved for adaptation to conditions of low oxygen. Acute adaptation includes increased ventilation, changes in metabolism, protection against hypoxia-induced cell death and vasodilation. Adaptations to chronic hypoxia are characterized by the aim to restore oxygen delivery to the tissue. This is achieved by improving the oxygen transport capacity by increasing haemoglobin and red blood cell mass. Furthermore, long-term adaptation includes the remodelling of existing vessels as well as the formation of new vessels to increase blood and concurrently oxygen supply. Most of the hypoxic adaptations implicate gene expression driven by transcription factors especially activated under hypoxic conditions, such as Hypoxia-inducible factor 1 (HIF-1). HIF-1 is the best characterized regulators of cellular responses to hypoxia and products of its target genes are involved in all phases of hypoxic adaptation. In addition, for certain tissues a variety of HIF-1 independent molecular changes contributing to the cellular hypoxic response have been described including activation of NF-κB, CREB, and Notch. Particular attention is devoted to a potential cross talk between the oxygen-dependent HIF-1 regulators prolyl-hydroxylase (PHDs) and these HIF-1 independent hypoxia regulated factors which are known to be critical for survival under general stress conditions.