The relationship between lymphangion chain length and maximum pressure generation established through in vivo imaging and computational modeling

Abstract

The intrinsic contraction of collecting lymphatic vessels serves as a pumping system to propel lymph against hydrostatic pressure gradients as it returns interstitial fluid to the venous circulation. In the present study, we proposed and validated that the maximum opposing outflow pressure along a chain of lymphangions at which flow can be achieved increases with the length of chain. Using minimally invasive near-infrared imaging to measure the effective pumping pressure at various locations in the rat tail, we demonstrated increases in pumping pressure along the length of the tail. Computational simulations based on a microstructurally motivated model of a chain of lymphangions informed from biaxial testing of isolated vessels was used to provide insights into the pumping mechanisms responsible for the pressure increases observed in vivo. These models suggest that the number of lymphangions in the chain and smooth muscle cell force generation play a significant role in determining the maximum outflow pressure, whereas the frequency of contraction has no effect. In vivo administration of nitric oxide attenuated lymphatic contraction, subsequently lowering the effective pumping pressure. Computational simulations suggest that the reduction in contractile strength of smooth muscle cells in the presence of nitric oxide can account for the reductions in outflow pressure observed along the lymphangion chain in vivo. Thus, combining modeling with multiple measurements of lymphatic pumping pressure provides a method for approximating intrinsic lymphatic muscle activity noninvasively in vivo while also providing insights into factors that determine the extent that a lymphangion chain can transport fluid against an adverse pressure gradient. NEW & NOTEWORTHY Here, we report the first minimally invasive in vivo measurements of the relationship between lymphangion chain length and lymphatic pumping pressure. We also provide the first in vivo validation of lumped parameter models of lymphangion chains previously developed through data obtained from isolated vessel testing.

Lymphatic Vessel Network Structure and Physiology

“…This was initially shown with measurements of pressures within lymphatic networks of exteriorized mesentery, which revealed that with each passage across a secondary valve to a downstream segment, intraluminal pressure increases gradually (415, 416, 1225). This concept was later confirmed in the rat tail with noninvasive near infrared imaging and computational modeling (892). Each step can be overcome by the phasic constriction of the lymphangion by its lymphatic smooth muscle layer.…”

A novel mouse tail lymphedema model for observing lymphatic pump failure during lymphedema development

“…Mice that swell significantly at any timepoint have sustained dysfunction in pumping pressure even as swelling returns close to baseline levels. Previous work combining computational and experimental data has shown that pumping pressure is a measurement of force generation of lymphatic muscle cells 25 . Low pumping pressure has also been described in humans with leg lymphedema, suggesting that a loss of collecting vessel pressure generation is correlated with the swelling experienced during lymphedema 26 .…”

Axial stretch regulates rat tail collecting lymphatic vessel contractions

“…To compare differences in collagen organization, image stacks were collected in the valvular and tubular regions; the tubular region was defined as 100 µm distance from the valve. Note that a typical rat tail is 3.3 mm 37 . The image z-stacks were imported in ZEN lite (Zeiss, Inc.) software to obtain 3D reconstructions.…”