This issue of the JCI contains the first articles in a Perspective series that focuses on ischemia, the major cause of mortality in the developed world. The specific mechanisms and consequences of ischemia differ in each tissue or organ, which reflects differences in anatomy and physiology. For this reason, the series has been organized to include articles on cerebral (Dennis Choi and colleagues), myocardial (Sandy Williams and Ivor Benjamin), and skeletal muscle (Jeff Isner) ischemia, as well as discussions of ischemia in epithelial tissues (Sanjay Nigam and colleagues) and hypoxia-induced pulmonary vascular remodeling (Norbert Voelkel and Rubin Tuder). In each case, the authors present a balanced overview of the field and focus on an area of particular interest, such as the contribution of excitatory neurotransmitter release to the pathogenesis of cerebral infarction, the protective effect of heat shock proteins (HSPs) in myocardial ischemia, the role of VEGF in ischemia-induced angiogenesis, the disruptive effects of ischemia on epithelial barrier function, or the effects of hypoxia on pulmonary vascular biology. Most of the research discussed employs tissue culture or small animal model systems and reflects the expectation that insights into basic pathophysiology will offer a foundation for designing therapeutics.

Despite the variability of responses to ischemia in various tissues, several general therapeutic strategies can be considered regardless of the anatomical site of ischemia. Ischemia arises when tissue demand for energy substrates (primarily O 2 and glucose) is not matched by supply, usually due to impaired perfusion. Thus, ischemia can be prevented or eliminated, in principle, by decreasing demand or increasing supply. As discussed by Williams and Benjamin, decreased demand occurs in the case of hibernating myocardium, in which the ATP-consuming process of contractility is inhibited to minimize O 2 and glucose consumption. Global inhibition of myocardial or cerebral function is unlikely to represent a viable therapeutic strategy, but the alternative of increasing supply to these tissues seems feasible, for example, by therapeutic angiogenesis (see Perspective by Isner). DNA-or protein-based clinical trials involving VEGF, other angiogenic factors, or mediators of their production are currently underway.