Non‐linear relationship between hyperpolarisation and relaxation enables long distance propagation of vasodilatation

Abstract

Non-technical summary Microvascular dilatations initiated locally in metabolically active tissues spread rapidly upstream, with little attenuation, to larger vessels whose relaxation results in the necessary increases in local blood flow. While this rapidly spreading response occurs due to the propagation of hyperpolarisation through gap junctions, it is not understood why the dilatation does not attenuate unless a regenerative electrical mechanism is involved. We show in skeletal muscle arterioles in vivo that no such regenerative electrical phenomenon exists. Instead, the local dilatation spreads without attenuation because the initial hyperpolarisation is supramaximal and the impact of voltage on dilatation is restricted to a narrow voltage window near the resting membrane potential. Knowledge of this mechanism increases our understanding of the processes which control blood flow to organs and explains how these processes can be compromised in diseases in which endothelial function is reduced.Abstract Blood flow is adjusted to tissue demand through rapidly ascending vasodilatations resulting from conduction of hyperpolarisation through vascular gap junctions. We investigated how these dilatations can spread without attenuation if mediated by an electrical signal. Cremaster muscle arterioles were studied in vivo by simultaneously measuring membrane potential and vessel diameter. Focal application of acetylcholine elicited hyperpolarisations which decayed passively with distance from the local site, while dilatation spread upstream without attenuation. Analysis of simultaneous recordings at the local site revealed that hyperpolarisation and dilatation were only linearly related over a restricted voltage range to a threshold potential, beyond which dilatation was maximal. Experimental data could be simulated in a computational model with electrotonic decay of hyperpolarisation but imposition of this threshold. The model was tested by reducing the amplitude of the local hyperpolarisation which led to entry into the linear range closer to the local site and decay of dilatation. Serial section electron microscopy and light dye treatment confirmed that the spread of dilatation occurred through the endothelium and that the two cell layers were tightly coupled. Generality of the mechanism was demonstrated by applying the model to the attenuated propagation of dilatation found in larger arteries. We conclude that long distance spread of locally initiated dilatations is not due to a regenerative electrical phenomenon, but rather a restricted linear relationship between voltage and vessel tone, which minimises the impact of electrotonic decay of voltage. Disease-related alterations in endothelial coupling or ion channel expression could therefore decrease the ability to adjust blood flow to meet metabolic demand.

The Vascular Conducted Response in Cerebral Blood Flow Regulation

“…This model, which gained support from experimental evidence in mouse cremaster arterioles in vivo, proposes that the conducted hyperpolarization is more negative than the range of membrane potentials at which L-type channel window currents occur, thus causing the vasodilatation to be maximal over a long segment of the arteriole, while the conducted hyperpolarization in fact decays electrotonically. 34 Thus, only at large distances from the local site is the hyperpolarization small enough to allow a limited Ca 2 þ entry through L-type channels, which would tend to decay the conducted vasodilatation. It will be interesting to see this model investigated in more vascular beds and using virtual arteriolar models incorporating the crucial ion channels and intercellular resistances known to affect conduction.…”

Origins of variation in conducted vasomotor responses

“…The well-coupled endothelium and the morphological layout of ECs and SMCs are known to be crucial for efficient electrical spread along the vascular wall [11, 17, 41]. Yet, despite decades of research, the question of why conduction is heterogeneous within and among vascular beds remain largely unresolved [8,9,14].…”

“…6 illustrates that conduction is affected by depolarization and the radial currents that arise due to different endogenous V m,rest (although the K-type endothelium may be somewhat hypothetical, arterioles of very hyperpolarized ECs have been observed [7,13]. Yet, the V m,rest evidently differs between vascular beds [9,16,36,41] and differences between the endogenous V m,rest of each layer are likely to occur). For instance, tonic discharge of noradrenaline from sympathetic nerves may depolarize the SMC layer.…”

“…Additional SMC layers The effect of additional SMC layers (all else being equal) has previously been shown to increase the electrical decay [26,41]. This is due to dilution of charge: increasing the number of cells that receives charge diminishes the V m -response in those cells.…”

Gap Junctions Suppress Electrical but Not [Ca 2+ ] Heterogeneity in Resistance Arteries

“…Cellular heterogeneity is ubiquitous in biological systems (1)(2)(3) and hence, is also manifest in the microcirculation (4)(5)(6)(7). Individual vascular cells display phenotypic variations due to random events that range from stochastic gene transcription to small fluctuations in the microenvironment.…”