No 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.

Diverse tree structures such as blood vessels, branches of a tree and river basins exist in nature. The constructal law states that the evolution of flow structures in nature has a tendency to facilitate flow. This study suggests a theoretical basis for evaluation of flow facilitation within vascular structure from the perspective of evolution. A novel evolution parameter (Ev) is proposed to quantify the flow capacity of vascular structures. Ev is defined as the ratio of the flow conductance of an evolving structure (configuration with imperfection) to the flow conductance of structure with least imperfection. Attaining higher Ev enables the structure to expedite flow circulation with less energy dissipation. For both Newtonian and non-Newtonian fluids, the evolution parameter was developed as a function of geometrical shape factors in laminar and turbulent fully developed flows. It was found that the non-Newtonian or Newtonian behavior of fluid as well as flow behavior such as laminar or turbulent behavior affects the evolution parameter. Using measured vascular morphometric data of various organs and species, the evolution parameter was calculated. The evolution parameter of the tree structures in biological systems was found to be in the range of 0.95 to 1. The conclusion is that various organs in various species have high capacity to facilitate flow within their respective vascular structures.

Lymphatic contractions play a fundamental role in maintaining tissue and organ homeostasis. The lymphatic system relies on orchestrated contraction of collecting lymphatic vessels, via lymphatic muscle cells and one-way valves, to transport lymph from the interstitial space back to the great veins, against an adverse pressure gradient. Circumferential stretch is known to regulate contractile function in collecting lymphatic vessels; however, less is known about the role of axial stretch in regulating contraction. It is likely that collecting lymphatic vessels are under axial strain in vivo and that the opening and closing of lymphatic valves leads to significant changes in axial strain throughout the pumping cycle. The purpose of this paper is to quantify the responsiveness of lympatic pumping to altered axial stretch. In situ measurements suggest that rat tail collecting lymphatic vessels are under an axial stretch of ~1.24 under normal physiological loads. Ex vivo experiments on isolated rat tail collecting lymphatics showed that the contractile metrics such as contractile amplitude, frequency, ejection fraction, and fractional pump flow are sensitive to axial stretch. Multiphoton microscopy showed that the predominant orientation of collagen fibers is in the axial direction, while lymphatic muscle cell nuclei and actin fibers are oriented in both circumferential and longitudinal directions, suggesting an axial component to contraction. Taken together, these results demonstrate the significance of axial stretch in lymphatic contractile function, suggest that axial stretch may play an important role in regulating lymph transport, and demonstrate that changes in axial strains could be an important factor in disease progression.

The structure-function relation is one of the oldest hypotheses in biology and medicine; i.e., form serves function and function influences form. Here, we derive and validate form-function relations for volume, length, flow, and mean transit time in vascular trees and capillary numbers of various organs and species. We define a vessel segment as a “stem” and the vascular tree supplied by the stem as a “crown.” We demonstrate form-function relations between the number of capillaries in a vascular network and the crown volume, crown length, and blood flow that perfuses the network. The scaling laws predict an exponential relationship between crown volume and the number of capillaries with the power, λ, of 4/3 < λ < 3/2. It is also shown that blood flow rate and vessel lengths are proportional to the number of capillaries in the entire stem-crown systems. The integration of the scaling laws then results in a relation between transit time and crown length and volume. The scaling laws are both intra-specific (i.e., within vasculatures of various organs, including heart, lung, mesentery, skeletal muscle and eye) and inter-specific (i.e., across various species, including rats, cats, rabbits, pigs, hamsters, and humans). This study is fundamental to understanding the physiological structure and function of vascular trees to transport blood, with significant implications for organ health and disease.