**Author details**

metabolic activity, such as macrophages, further depletes the oxygen availability, creating a hypoxic environment in the atherosclerotic lesion. In macrophages, hypoxia not only affects the metabolism and lipid uptake but also results in an increased inflammatory response characterized by increased IL-1β and caspase-1 activation. Hypoxia also augments the thrombo-

The identification of specific inflammatory markers pertaining to the arterial wall in atherosclerosis may be useful for both diagnosis and treatment. These include macrophage inhibiting factor (MIF), leucocytes and P-selectin. Purinergic signalling is involved in the control of vascular tone and remodelling. Endothelial cells release purines and pyrimidines in response to changes in blood flow (evoking shear stress) and hypoxia. They then act on P2Y, P2X and P1 receptors on endothelial cells leading to release of EDRF mediated by nitric oxide and prostaglandins and EDHF, resulting in vasodilatation. The therapeutic potential of purinergic compounds for the treatment of vascular diseases, including hypertension, ischaemia, atherosclerosis, migraine and coronary artery and diabetic vascular disease as well as vasospasm is discussed [82]. Modern therapeutic modalities involving endothelial progenitor cells therapy, angiotensin II type-2 (AT2R) and ATP-activated purinergic receptor therapy are notable to mention. Future drugs may be designed to target three signalling mechanisms of AT2R which are (a) activation of protein phosphatases resulting in protein dephosphorylation, (b) activation of bradykinin/nitric oxide/ cyclic guanosine 3˝,5˝-monophosphate pathway by vasodilation and (c) stimulation of phospholipase A(2) and release of arachidonic acid. Drugs may also be designed to act on ATP-activated purinergic receptor channel type P2X7 molecules which acts on cardiovascular system. Better understanding of the vascular inflammatory processes and the cells involved in the formation of plaques may prove to be beneficial for future diagnosis, clini-

genic potential of atherosclerotic plaques through upregulation of tissue factor.

124 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

cal treatment and planning innovative novel anti-atherosclerotic drugs [83].

some novel therapeutic approaches to the treatment of cardiovascular disease.

metabolism [84].

**5. Conclusion**

Systemic hypoxia that is, for example, associated with obstructive sleep apnoea (OSA) also promotes atherosclerosis. The processes by which it may do this include effects on lipid metabolism and efflux, inflammation, altered macrophage polarization and glucose

Hypoxia is involved in several pathophysiological processes, including embryogenesis, angiogenesis and atherogenesis. HIF-1 appears to be an important mediator controlling cellular response to hypoxia. It also appears to be related to atherosclerotic progression and rupture. A better understanding of the mechanism involved in these processes may provide Lamia Heikal \* and Gordon Ferns

\*Address all correspondence to: l.heikal@bsms.ac.uk

Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom

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**Provisional chapter**
