Mechanobiological oscillators control lymph flow

Abstract

The ability of cells to sense and respond to physical forces has been recognized for decades, but researchers are only beginning to appreciate the fundamental importance of mechanical signals in biology. At the larger scale, there has been increased interest in the collective organization of cells and their ability to produce complex, "emergent" behaviors. Often, these complex behaviors result in tissue-level control mechanisms that manifest as biological oscillators, such as observed in fireflies, heartbeats, and circadian rhythms. In many cases, these complex, collective behaviors are controlled-at least in part-by physical forces imposed on the tissue or created by the cells. Here, we use mathematical simulations to show that two complementary mechanobiological oscillators are sufficient to control fluid transport in the lymphatic system: Ca 2+ -mediated contractions can be triggered by vessel stretch, whereas nitric oxide produced in response to the resulting fluid shear stress causes the lymphatic vessel to relax locally. Our model predicts that the Ca 2+ and NO levels alternate spatiotemporally, establishing complementary feedback loops, and that the resulting phasic contractions drive lymph flow. We show that this mechanism is self-regulating and robust over a range of fluid pressure environments, allowing the lymphatic vessels to provide pumping when needed but remain open when flow can be driven by tissue pressure or gravity. Our simulations accurately reproduce the responses to pressure challenges and signaling pathway manipulations observed experimentally, providing an integrated conceptual framework for lymphatic function.

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).…”

“…Interestingly, increasing the volume of fluid injected in the footpad reduced the NIR frequency and contraction frequency (Figure 2D and Figure 3F). This is likely due to increases in pressure, stretch of the vessel and/or increased shear as greater volumes are injected (25,28). It has previously been hypothesized that increasing tissue pressure increases lymphatic pressure (27).…”

The Lymphatic System in Disease Processes and Cancer Progression

“…The fact that NO is produced through endothelial nitric oxide synthase (eNOS) in response to fluid shear forces allows it to establish another mechanobiological feedback system that, together with stretch-activated calcium channels, can help control the phasic contractions (91). Endothelium-derived relaxing factors such as NO provide a counterbalance to calcium-induced contractions, maintaining vessel dilation in circumstances when low resistance is needed to allow pressure-driven flow (78).…”

“…Computational modeling shows that the mechanosensitive calcium and NO dynamics can cooperate to control lymphatic transport via mechanobiological feedback loops (91): During a lymphatic contraction cycle, increased flow causes local eNOS activation, and the subsequent production of NO attenuates and/or reverses the Ca 2+ -dependent contraction (Figure 3). As the vessel relaxes, NO degrades rapidly and its production drops due to the reduced fluid velocity in the now-larger-diameter vessel.…”