In recent years, it has become clear that mitochondria play a central role in several aspects of animal physiology and pathophysiology (18). Although the main role of mitochondria is to produce ATP, additional roles have recently been recognized. Mitochondria take up Ca2+ and play a key role in cellular Ca2+ homeostasis; the high capacity of mitochondrial Ca2+ uptake provides a means of matching energy demand with ATP production, since several mitochondrial enzymes are activated by Ca2+ (18). Mitochondria have also been proposed as important 02 sensors in a variety of 02-sensitive tissues, including the pulmonary arteries, the ductus arteriosus, and the carotid body (3). The role ofmitochondria as 02 sensors (see Chapter 9) allows them to match energy (or 02) demand with 02 delivery in the body, either by optimizing ventilation-perfusion matching (via hypoxic pulmonary vasoconstriction) or 02 delivery (via activation of the brain respiration center by the carotid body). An important factor in the mitochondria-based 02 sensing pathways is the activated oxygen species (AOS) produced in the mitochondrial electron transport chain (ETC). Some AOS, like hydrogen peroxide (H202), have a long effective diffusion radius and can leak to the cytosol and membrane and activate second messengers and ion channels that control vascular tone (3). Furthermore, mitochondria are recognized as a key regulator of apoptosis (22), a critical factor in the development or regression of pulmonary vascular remodeling (15, 28). By being involved in the regulation of both vascular tone and vascular remodeling, mitochondria might be more important in vascular disease than currently recognized and will undoubtedly be excellent targets for drug development.
There is definitive evidence that mitochondrial diversity exists among different organs or tissues. In addition to summarizing the existing evidence for such diversity, this chapter introduces the concept of mitochondrial diversity in the vasculature. We discuss recently published evidence that mitochondria are different between the vascular smooth muscle cells (SMC) in pulmonary versus systemic arteries. Such diversity might at least in part explain the still unresolved "mystery" of why the pulmonary arteries (PA) constrict to hypoxia while the systemic arteries dilate or why the pulmonary circulatory system is a "low pressure" circulation compared to the systemic circulatory system. Furthermore, this diversity might provide clues for the development of drugs that will target the pulmonary but not the systemic arteries, a much-desired feature of the ideal candidate treatment for pulmonary arterial hypertension.
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