Synchronization and Random Triggering of Lymphatic Vessel Contractions

Abstract

The lymphatic system is responsible for transporting interstitial fluid back to the bloodstream, but unlike the cardiovascular system, lacks a centralized pump-the heart–to drive flow. Instead, each collecting lymphatic vessel can individually contract and dilate producing unidirectional flow enforced by intraluminal check valves. Due to the large number and spatial distribution of such pumps, high-level coordination would be unwieldy. This leads to the question of how each segment of lymphatic vessel responds to local signals that can contribute to the coordination of pumping on a network basis. Beginning with elementary fluid mechanics and known cellular behaviors, we show that two complementary oscillators emerge from i) mechanical stretch with calcium ion transport and ii) fluid shear stress induced nitric oxide production (NO). Using numerical simulation and linear stability analysis we show that the newly identified shear-NO oscillator shares similarities with the well-known Van der Pol oscillator, but has unique characteristics. Depending on the operating conditions, the shear-NO process may i) be inherently stable, ii) oscillate spontaneously in response to random disturbances or iii) synchronize with weak periodic stimuli. When the complementary shear-driven and stretch-driven oscillators interact, either may dominate, producing a rich family of behaviors similar to those observed in vivo.

Lymphatic function measurements influenced by contrast agent volume and body position

“…NIRF imaging showed that the lowest contraction frequency was measured after an injection of 20 μl of contrast agent ( Figure 2D). This is similar to what others have reported in ex vivo measurements of lymphatic vessels when a favorable pressure gradient was imposed, likely causing a shear-dependent response (18,20,(24)(25)(26). (Figure 2, A-D and Supplemental Videos 1-3; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.96591DS1).…”

“…Lymphatic contraction reduction in the presence of increased flow suggests there is flow-mediated dilation and contraction inhibition due to the presence of a favorable upstream pressure gradient, which has been reported via ex vivo analysis of lymphatic vessels subjected to step-wise increasing pressures (18,20,(24)(25)(26). Similar results of increased lymph flow have been reported with intravital imaging of rats experiencing edemagenic stress (30).…”

The effects of valve leaflet mechanics on lymphatic pumping assessed using numerical simulations

“…Our previous work has elucidated how these behaviors are coordinated throughout the lymphatic system by mechano-sensitive feedback 15,16 . In summary, our model shows that and NO concentrations establish complementary and oscillatory feedback loops that are self-regulating, maintaining normal lymphatic function, in agreement with experimental observations 12,17–19 .…”

A one-dimensional mathematical model of collecting lymphatics coupled with an electro-fluid-mechanical contraction model and valve dynamics

“…The resulting model was able to control lymphatic transport via mechanobiological feedback loops, given by stretch-activated contractions and flow-induced relaxations. Very recently, Baish et al [83] proposed a model of a vascular oscillator and studied the interaction of Ca 2+ and NO in the context of lymphatic vessel contractions.…”

“…With the aim of constructing a mathematical model of the entire lymphatic system, the above-mentioned mathematical models for lymphangions, except for [14,83], are based on a relatively simple contraction dynamic. As a matter of fact, these models 1) prescribe muscle contractility dynamics by using trigonometric functions, and 2) artificially prescribe time delays between adjacent lymphangions.…”