Spreading the signal for vasodilatation: Implications for skeletal muscle blood flow control and the effects of ageing

Blood flow control requires coordinated contraction and relaxation of smooth muscle cells (SMCs) along and among the arterioles and feed arteries that comprise vascular resistance networks. Whereas smooth muscle contraction of resistance vessels is enhanced by noradrenaline release along perivascular sympathetic nerves, the endothelium is integral to coordinating smooth muscle relaxation. Beyond producing nitric oxide in response to agonists and shear stress, endothelial cells (ECs) provide an effective conduit for conducting hyperpolarization along vessel branches and into surrounding SMCs through myoendothelial coupling. In turn, bidirectional signalling from SMCs into ECs enables the endothelium to moderate adrenergic vasoconstriction in response to sympathetic nerve activity. This review focuses on the endothelium as the cellular pathway that coordinates spreading vasodilatation. We discuss the nature and regulation of cell-to-cell coupling through gap junctions, bidirectional signalling between ECs and SMCs, and how oxidative stress during ageing may influence respective signalling pathways. Our recent findings illustrate the role of small (SK_Ca) and intermediate (IK_Ca) Ca²⁺ activated K⁺ channels as modulators of electrical conduction along the endothelium. Gaps in current understanding indicate the need to determine mechanisms that regulate intracellular Ca²⁺ homeostasis and ion channel activation in the resistance vasculature with advancing age.