TRP channels: a provocative rationalization for local Ca2+ control in arterial tone development

Abstract

Arterial networks are controlled by the consolidated output of stimuli that set “how much” (magnitude) and “where” (distribution) blood flow is delivered. While notable changes in magnitude are tied to network wide responses, altered distribution often arises from focal changes in tone, whose mechanistic foundation remains unclear. We propose herein a framework of focal vasomotor contractility being controlled by pharmacomechanical coupling and the generation of Ca2+ waves via the sarcoplasmic reticulum. We argue the latter is sustained by receptor operated, transient receptor potential (TRP) channels through direct extracellular Ca2+ influx or indirect Na+ influx, reversing the Na+/Ca2+ exchanger. We view this focal regulatory mechanism as complementary, but not redundant with, electromechanical coupling in the precision tuning of blood flow delivery.

Functional Bias of Contractile Control in Mouse Resistance Arteries

“…This shift to pharmacomechanical dominance was also evident in our [Ca 2+ ] i measures; focal application elicited a modest, nifedipine-insensitive rise whereas the large change induced by global application was abolished by this L-type Ca 2+ channel blocker (Figure 9). While the mechanisms driving the voltage-insensitive [Ca 2+ ] i responses are unclear, past studies have implied a role for: 1) receptor operated, transient receptor potential channels; or 2) Ca 2+ waves, asynchronous events that originate from the sarcoplasmic reticulum 6,8,57 .…”

“…In this scenario, hyperpolarizing responses, due to feedback loops or endothelial activation, would lose their ability to fully dilate an artery. Moderation of pharmacomechanical control would require an alternative nonelectrical mechanism, perhaps one tied to nitric oxide and protein kinase G, which could conceivably limit MLCP inhibition by interfering with MYPT1 phosphorylation 57,58,59 . Note, if agent concentration was high and focal enough, the result of local varicosity release, intrinsic tissue production or injury, small arterial segments would expectantly operate independent of the broader network, to tune blood flow distribution discretely and markedly to defined regions 60 .…”