Integration and Modulation of Intercellular Signaling Underlying Blood Flow Control.

Vascular resistance networks control tissue blood flow in concert with regulating arterial perfusion pressure. In response to increased metabolic demand, vasodilation arising in arteriolar networks ascends to encompass proximal feed arteries. By reducing resistance upstream, ascending vasodilation (AVD) increases blood flow into the microcirculation. Once initiated, e.g. through local activation of K(+) channels in endothelial cells (ECs), hyperpolarization is conducted through gap junctions along the endothelium. Via EC projections through the internal elastic lamina, hyperpolarization spreads into the surrounding smooth-muscle cells (SMCs) through myoendothelial gap junctions (MEGJs) to promote their relaxation. Intercellular signaling through electrical signal transmission (i.e. cell-to-cell conduction) can thereby coordinate vasodilation along and among the branches of microvascular resistance networks. Perivascular sympathetic nerve fibers course through the adventitia and release norepinephrine to stimulate SMCs via α-adrenoreceptors to produce contraction. In turn, SMCs can signal ECs through MEGJs to activate K(+) channels and attenuate sympathetic vasoconstriction. Activation of K(+) channels along the endothelium will dissipate electrical signal transmission and inhibit AVD, thereby restricting blood flow into the microcirculation while maintaining peripheral resistance and perfusion pressure. This review explores the origins and nature of the intercellular signaling that governs blood flow control in skeletal muscle with respect to the interplay between AVD and sympathetic innervation. Whereas these interactions are integral to daily activity and athletic performance, determining the interplay between respective signaling events provides insight into how selective interventions can improve tissue perfusion and oxygen delivery during vascular disease.