Publications

A paradigm shift for local blood flow regulation

Abstract

A remarkable example of physiological regulation is the coordination between metabolic rate and local blood flow in microscopic volumes of an organ. In skeletal muscle an increase in oxygen consumption (V̇o2) over a wide range evokes a proportional (∼5 to 6 × V̇o2) increase in blood flow (29). In the brain, neurovascular coupling is the basis for noninvasive blood flow methods (e.g., fMRI) for imaging functionally active brain regions with high spatial and temporal resolution. However, the phenomenon of local functional hyperemia in skeletal muscle and in brain still has no reliable mechanistic rationale. The historically established metabolic theory of local blood flow regulation assumes the existence of basal tone in arterioles (Fig. 1, top). An increase in cell respiration leads to a drop in tissue/cellular Po2 and then to the production of vasodilator metabolites by parenchymal cells, which increase local blood flow via a negative feedback control (30, 31, 33). However, this mechanism implies that the restoration of an adequate oxygen supply stops the production of the metabolic signal, which should then reduce local blood flow. The drawback of this model is the inevitable maintenance of tissue hypoxia. A key issue for the traditional metabolic theory is a failure to confirm the necessary components for this mechanism of regulation: an active closure of capillaries and significant change in capillary density (14, 18, 28), a functional role for precapillary sphincters (10), and certain metabolic vasodilator(s) produced by parenchymal cells during hypoxia (31, 32). Because of its reliance on tissue-produced vasodilators, the old metabolic theory cannot incorporate new knowledge about the action of the signaling radical superoxide (O2−) and nitric oxide (NO), a strong vasodilator produced by the vascular endothelium and not by tissue cells.