Regulation of peripheral vascular function: the role of the capillaries in microvascular control

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Any tissue inadequately perfused with blood will fail. Matching blood flow to changing metabolic demand is critical for proper cellular and tissue function, and critical to prevent damage. This process requires a system of communication whereby tissues can signal the vasculature that an increase in metabolic rate is occurring, and the vasculature can respond by increasing blood flow accordingly. The brain and skeletal muscle require particularly sophisticated communication with the vasculature because it is possible for one part of these tissues to be active while others are not; blood flow must therefore be directed specifically to active regions and no the tissue as a whole. This careful targeting of blood flow within the tissue requires (i) an active cell communicate its need for increased oxygen to the microvasculature, and (ii) intercommunication within the microvasculature network to direct blood flow to the active cell. Our basic understanding of how these important processes happen is surprisingly incomplete. Over the next 5 years my research program will address these critical knowledge gaps, using skeletal muscle as a model and advanced methods in intravital microscopy and immunohistochemistry. First, we will explore how capillary endothelial cells respond to different types of molecular signals relevant to muscle contraction and whether all capillary endothelial cells respond in the same way. Second, we will determine how capillaries communicate with upstream arterioles. Our lab has recently discovered a pannexin-dependent communication pathway that facilitates capillary communication with upstream arterioles; we now need to characterize this this pathway within the microvascular network to fully understand its functionality. Finally, we will determine how upstream arterioles communicate with each other to cause vasodilation of very specific arterioles to promote blood flow to active skeletal muscle fibres only. We will do this by determining how the pannexin pathway integrates with the existing connexin-dependent communication pathway already characterized. This research will be the first to explore novel characteristics of capillaries and their role in coordinating blood flow during muscle contraction to match metabolic requirements. Research in this area has traditionally focused on the arterioles; our work will refocus the field onto capillaries as the locus of control of blood flow, opening the door to research directions never before considered. Moreover, this work is highly translatable to other tissues, as matching of oxygen delivery to demand is a universal problem in all tissues and essential to normal functioning. Given that impaired oxygen delivery is a significant feature of many acute and chronic diseases, our research also offers new potential to understand the dysregulation of blood flow control.