The circulatory physiopathology of human red blood cells investigated with a multiplatform model of cellular homeostasis. II. Capillary transits and the role of PIEZO1

Abstract

Capillary transit times vary between 0.5 and 1.5s during which the red blood cells squeeze and deform in the capillary stream transiently opening stress-gated PIEZO1 channels, creating minuscule quantal changes in RBC ion contents and volume. Ideas originally advanced four decades ago and widely assumed to be correct suggested that quantal changes generated during capillary transits add up over time to generate the documented changes in RBC density during their long circulatory lifespan, the quantal hypothesis. Applying the new PIEZO1 extension of the RBC model (RCM) introduced in the previous paper we investigate here in detail the changes in homeostatic variables that may be expected during single capillary transits resulting from transient PIEZO1 channel activation. The results showed that quantal volume changes were infinitesimal in magnitude, biphasic in nature, and essentially irreversible within inter-transit periods. A sub-second transient PIEZO1 activation triggered a sharp swelling peak followed by a much slower dehydration period towards lower-than-baseline volumes. The peak response was caused by net CaCl 2 and fluid gain via PIEZO1 channels driven by the steep electrochemical inward Ca 2+ gradient. The ensuing dehydration followed a complex time-course with sequential, but partially overlapping contributions by KCl loss via Ca 2+ -activated Gardos channels, PMCA mediated calcium extrusion and chloride efflux by the Jacobs-Steward mechanism. The change in relative cell volume predicted for single capillary transits was below 10 -4 , an infinitesimal magnitude incompatible with a functional role in capillary flow. The biphasic response predicted by the RCM appears to conform to the quantal hypothesis, but whether its cumulative effects could account for the documented changes in density during RBC senescence required an investigation of the effects of myriad transits over the full period of circulatory lifespan, the subject of the next paper of this series.

Up-down biphasic volume response of human red blood cells to PIEZO1 activation during capillary transits

“…It is important to stress here that the attribution of an anion conductance to PIEZO1 (PzA) is only intended as a means to implement a minimalist phenomenology that enables us to investigate the need or otherwise to associate the changes in PIEZO1-mediated cation and anion permeabilities during the PIEZO1 open state in the simulations. As will become apparent in this and the following paper [ 1 ], the results do support a strong association between increased cation and anion permeabilities during the PIEZO1 open states. However, the model results carry no information on whether the anion permeability is through PIEZO1, as PzA may imply, or through another PxA pathway.…”

“…Together with the large body of early data it has now become possible to constrain the parameter space sufficiently and attempt a computational modelling approach to unravel the mechanisms behind the homeostasis changes individual RBCs experience throughout the myriad capillary transits in the circulation. The results of this investigation, reported in this and the next paper [ 1 ], present an entirely new and unexpected perspective on the coordinated roles played by five RBC membrane transporters to enable the long circulatory lifespan of RBCs. We briefly review next relevant background information on the model and on red blood cells homeostasis.…”

“…Because transit times are so much shorter (< 2s) than inter-transit periods (1–2 min) it may be questionable whether the brief high-CVF transitions could generate relevant effects, a question answerable only by comparing predicted outcomes with high and low CVF values during capillary transits. As we shall see, negligible effects at single capillary transits turned out to be of cumulative relevance over lifespans [ 1 ].…”

“…The default permeability values set for the Ref routine were: PzCa, 70h -1 ; PzA, 50h -1 ; and zero for PzNa and PzK. The reasons for these choices will become clear with the analysis of the results in this paper; a full explanation for the value of 70h -1 attributed to the reference PzCa will have to await the analysis in the section on “Hyperdense collapse” in the companion paper [ 1 ], where it is shown that PzCa values compatible with observed lifespan densification patterns and cell integrity cannot exceed certain maximal values, as with the 70h -1 value linked to a PIEZO1 open state duration of 0.4s in the reference protocol.…”

“…Deformability, in turn, depends on the RBCs maintaining their volume well below their maximal spherical volume (reduced volume), a condition fulfilled when their reduced volume is kept within a narrow margin around 60% [ 6 , 7 ]. For human RBCs with a mean circulatory lifespan of about 120 days, this represents a substantial challenge, and the mechanism by which this is achieved is the subject of the investigation in this and the next paper [ 1 ].…”