Microcirculation, 12: 33–45, 2005 Copyright c  2005 Taylor & Francis Inc. ISSN: 1073-9688 print / 1549-8719 online DOI: 10.1080/10739680590895028 Regulation of Blood Flow in the Microcirculation STEVEN S. SEGAL The John B. Pierce Laboratory & Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA ABSTRACT The regulation of blood flow has rich history of investigation and is exemplified in exercising skeletal muscle by a concerted interaction between striated muscle fibers and their microvascular supply. This review considers blood flow control in light of the regulation of capillary perfusion by and among terminal arterioles, the distribution of blood flow in arteriolar networks according to metabolic and hemodynamic feedback from active muscle fibers, and the balance between peak muscle blood flow and arterial blood pressure governed by sympathetic nerve activity. As metabolic demand increases, the locus of regulating oxygen delivery to muscle fibers “ascends’’ from terminal arterioles, through intermediate distributing arterioles, and into the proximal arterioles and feed arteries, which govern total flow into a muscle. At multiple levels, venules are positioned to provide feedback to nearby arte- rioles regarding the metabolic state of the tissue through the convection, production and diffusion of vasodilator stimuli. Electrical signals initiated on microvascular smooth muscle and endothelial cells can travel rapidly for millimeters through cell-to-cell conduction via gap junction channels, rapidly coordinating vasodilator responses that govern the distribution and magnitude of blood flow to active muscle fibers. Sympathetic constriction of proximal arterioles and feed arteries can restrict functional hyperemia while dilation prevails in distal arterioles to promote oxygen extraction. With vasomotor tone reflecting myogenic contraction of smooth muscle cells modulated by shear stress on the en- dothelium, the initiation of functional vasodilation and its modulation by sympathetic innervation dictate how and where blood flow is distributed in response to metabolic demand. A remarkable ensemble of signaling pathways underlies the integration of smooth muscle and endothelial cell func- tion in microvascular networks. These pathways are being defined with refreshing new insight as novel approaches are applied to understanding the cellular and molecular mechanisms of blood flow control. Microcirculation (2005) 12, 33–45. doi:10.1080/10739680590895028 KEY WORDS: arteriole, capillary, exercise, skeletal muscle, sympathetic nerves, venule INTRODUCTION The regulation of blood flow has rich history of inves- tigation and is exemplified in exercising skeletal mus- cle by a concerted interaction between striated mus- cle fibers and their microvascular supply (Figure 1). In this review, the microcirculation of skeletal mus- cle is emphasized because of its tremendous dynamic range of blood flow. Indeed, from being restricted by The author’s research is supported by the United States Pub- lic Health Service, National Institutes of Health grants RO1- HL41026, RO1-HL56786, and R21-AG19347. The contributions of Tonya Jacobs and Shawn Bearden to acquiring Figures 1 and 2 are gratefully acknowledged. Address correspondence to Steven S. Segal, PhD, The John B. Pierce Laboratory, Yale University School of Medicine, 290 Congress Ave, New Haven, CT 06519, USA. E-mail: sssegal@ jbpierce.org Received 1 July 2004; accepted 30 September 2004. sympathetic nerve activity at rest to maximal hyper- emia during intense aerobic exercise, muscle blood flow can change nearly 100-fold (109). Within the microcirculation, the distribution and magnitude of blood flow represent a coordinated interplay between arteriolar, capillary, and venular segments accord- ing to local and regional metabolic demand. In turn, mechanisms of flow control reflect the functional in- teractions between skeletal muscle fibers and the re- spective smooth muscle cells, endothelial cells, and neural projections, which comprise and regulate the vascular supply. The regulation of muscle blood flow is presented in context of the classic Fick relation- ship, where the consumption of oxygen by the mito- chondria within muscle fibers reflects the product of extraction from the blood and the rate of blood flow through the muscle (105). This review begins by con- sidering the microvascular determinants of oxygen extraction and progresses into exploring how the level of blood flow is governed according to the metabolic