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.
Highlights
To maintain fluid homeostasis, interstitial fluid drains into the lymphatic system through initial lymphatic vessels that carry it to the collecting lymphatic vessels
The lymphatic system is receiving similar attention as more is learned about its functional role in disease processes
The importance of the lymphatic system in collecting excess fluid from tissues and returning it to the blood is well known, but how the lymph flow is regulated without a central pump is poorly understood
Summary
Interstitial fluid drains into the lymphatic system through initial lymphatic vessels that carry it to the collecting lymphatic vessels. The collecting lymphatic vessels transport the fluid (known as lymph) both passively and actively to lymph nodes and back to the systemic blood circulation. Collecting lymphatic vessels are surrounded by specialized lymphatic muscle cells (LMCs) [1] and sub-divided by valve structures that define individual segments called lymphangions (Fig 1) [2]. Lymphangions serve as both pumps and conduits. The effects of Ca2+ on LMC contraction are moderated by endothelial-derived relaxation factors (EDRFs) that act as potent dilators of lymphatic and blood vessels when produced by the vessel-lining lymphatic endothelial cells (LECs) in response to dynamic fluid shear stresses. We previously used a relatively complex numerical simulation of lymphatic pumping to demonstrate that a wide spectrum of oscillatory behaviors is possible, and that the behavior is very sensitive to local levels of stretch and stress [11]
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