**1. Introduction**

The circulatory system develops early in mammalian embryogenesis. An oxygen supply is essential for normal tissue function, development and homeostasis. The vascular network within the cardiovascular system is essential for the delivery of oxygen, nutrients and other molecules to the tissues of the body [1]. Oxygen availability serves as an important regulator of the cardiovascular system. Oxygen balance may be perturbed if there is reduced oxygen diffusion, or increased oxygen consumption that may be a consequence of rapid cellular divi-

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

sion during embryonic development, by tumour growth, or by vasculature dysfunction due to vessel occlusion or rupture [2].

Hypoxia is defined by a reduced oxygen tension relative to those normally extant within a particular tissue. It has multiple impacts on the vascular system and cell function [3]. The effects of moderate hypoxia (3–5% O<sup>2</sup> ) are usually reversible and are usually accompanied by adaptive physiological responses in the cells. A lower oxygen tension (0–1% O<sup>2</sup> ) contributes to the pathophysiology of tumour progression and cell apoptosis [4] and is a feature of conditions that include cancer, ischemic heart disease, peripheral artery disease, wound healing and neovascular retinopathy. Hypoxia promotes vessel growth by stimulating an upregulation of multiple proangiogenic pathways that mediate key aspects of endothelial, stromal and vascular support cell biology. The role of hypoxia in human disease is now becoming increasingly clear [5] including the association between hypoxia and endothelial dysfunction that affects several cellular processes and signal transduction.

Hypoxia can occur in several ways: (1) hypoxic hypoxia is caused by an insufficient oxygen concentration in the air in the lungs, which may occur during sleep apnea, when the diffusion of oxygen to the blood is reduced, or at high altitude; (2) hypoxemic hypoxia occurs when the blood has reduced transport capacity as seen in carbon monoxide poisoning when haemoglobin cannot carry oxygen at its normal concentrations; (3) stagnant hypoxia results when the cardiac output does not match the demands of the body and the flow is not sufficient to deliver enough oxygenated blood to the tissue and (4) histotoxic hypoxia occurs when cells cannot utilize the available oxygen, for example following cyanide poisoning when oxygen cannot be used to produce ATP as the mitochondrial electron transport is inhibited.

Chronic tissue hypoxia (an oxygen tension of 2–3% for a prolonged period of time) may cause uncontrolled proliferation of cells. When physiological oxygen concentrations are restored, the increased blood flow supplies excessive oxygen; this may then lead to increased freeradical generation, tissue damage and concomitant activation of stress-response genes; a condition known as 'reoxygenation injury'. In these circumstances, normal cells/tissues may not survive; but tumour cells are still able to proliferate despite the hypoxic milieu, as they have developed genetic and adaptive changes leading to resistance to hypoxia [6].

Hypoxia plays important roles in normal human physiology and development. For example, it is integral to normal embryonic development. Whatever the cause, or the severity of hypoxia, it leads to an induction of adaptive responses within the endothelial and vascular smooth muscle cells through the activation of genes that participate in angiogenesis, cell proliferation/survival and in glucose and iron metabolism [7].

In healthy vascular tissue, vascular smooth muscle cells (SMCs) and endothelial cells (ECs) proliferate at very low levels. However, SMCs and ECs can be stimulated to re-enter the cell cycle in response to several physiological and pathological stimuli. Hypoxia is considered an important stimulus of SMC and EC proliferation and is found in atherosclerotic lesions and rapidly growing tumours [4].

The proliferation of ECs is pivotal to the formation of new micro-vessels and is important during organ development in embryogenesis and tumour growth, and also contributes to diabetic retinopathy, psoriasis, rheumatoid arthritis and atherosclerosis. Abnormal SMC proliferation contributes to atherosclerosis, intimal hyperplasia after angioplasty and graft atherosclerosis after coronary transplantation [8, 9].
