Confocal Image-Based Computational Modeling of Nitric Oxide Transport in a Rat Mesenteric Lymphatic Vessel

Abstract

The lymphatic system plays important roles in protein and solute transport as well as in the immune system. Its functionality is vital to proper homeostasis and fluid balance. Lymph may be propelled by intrinsic (active) vessel pumping or passive compression from external tissue movement. With regard to the former, nitric oxide (NO) is known to play an important role modulating lymphatic vessel contraction and vasodilation. Lymphatic endothelial cells (LECs) are sensitive to shear, and increases in flow have been shown to cause enhanced production of NO by LECs. Additionally, high concentrations of NO have been experimentally observed in the sinus region of mesenteric lymphatic vessels. A computational flow and mass transfer model using physiologic geometries obtained from confocal images of a rat mesenteric lymphatic vessel was developed to determine the characteristics of NO transport in the lymphatic flow regime. Both steady and unsteady analyses were performed. Production of NO was shear-dependent; basal cases using constant production were also generated. Simulations revealed areas of flow stagnation adjacent to the valve leaflets, suggesting the high concentrations observed here experimentally are due to minimal convection in this region. LEC sensitivity to shear was found to alter the concentration of NO in the vessel, and the convective forces were found to profoundly affect the concentration of NO at a Péclet value greater than approximately 61. The quasisteady analysis was able to resolve wall shear stress within 0.15% of the unsteady case. However, the percent difference between unsteady and quasisteady conditions was higher for NO concentration (6.7%). We have shown high NO concentrations adjacent to the valve leaflets are most likely due to flow-mediated processes rather than differential production by shear-sensitive LECs. Additionally, this model supports experimental findings of shear-dependent production, since removing shear dependence resulted in concentrations that are physiologically counterintuitive. Understanding the transport mechanisms and flow regimes in the lymphatic vasculature could help in the development of therapeutics to treat lymphatic disorders.

Lymph flow pattern in pleural diaphragmatic lymphatics during intrinsic and extrinsic isotonic contraction

“…9B, the electrical stimulation is indeed able to elicit a change in the intrinsic pumping pattern, increasing net forward lymph progression. These observations can be explained based on the following considerations: 1) the shear stress is very low in these vessels and, even during extrinsic contraction, never exceeds 0.25 dyne/cm 2 (Table 1), a value that might be below the threshold for the induction of nitric oxide production (14,32,41); and 2) the source of the electrical stimulus was artificial in our experiments, and it cannot be excluded that the electrical activity of the skeletal muscle could also affect the intrinsic contraction on purely electrical basis, implying a potential electrical interplay between the two pumping mechanisms.…”

Primary and secondary lymphatic valve development: Molecular, functional and mechanical insights

“…Increasing shear stress stimulates the production of NO by LECs (Bohlen et al, 2011; Bohlen et al, 2009) causing hyperpolarization of LMCs, which inhibits the pacemaker activity due to increased cGMP levels (von der Weid, 1998; von der Weid et al, 2001). Interestingly, computational modeling of NO transport in the valvular area of the lymphangion has demonstrated that the high NO concentration observed there is attributed to flow stagnation in these locations (Figure 3, left) (Wilson et al, 2013). Due to the highly viscous nature of the flow, fluid filling the space behind the valve leaflets is essentially stagnant (although it does move in slowly rotating vortex-like structures).…”

“…Note that Wilson et al prescribed that NO production increases with flow-induced shear stress, so the LECs in the stagnant zone are actually producing less NO than those exposed to the mainstream of the flow, especially on the inner surface of the valve leaflets (Figure 3, right). Thus, the flow phenomena end up being the major determinants of NO concentration distribution and could possibly affect other signaling pathways (Wilson et al, 2013). As this study was done with a stationary geometry, it remains to be determined how the motion of the leaflets towards the wall or back to the center of the lumen might influence these predicted NO distribution patterns.…”

“…2" rend="display" xml:id="FD2">$$Re=\frac{\text{VD}}{\mathrm{\nu }},$$ where V is the velocity, D is diameter and ν is the kinematic viscosity of the fluid in this situation, represents the ratio of intertial to viscous forces. It is generally less than one in the lymphatic flow regime (Dixon et al, 2006; Wilson et al, 2013), indicating the valves must operate under highly viscous flow conditions. Turbulence typically does not begin to develop in straight tubes until Re approaches 2000.…”

“…NO concentration values are normalized by a characteristic inlet concentration, Co. While streamlines adjacent to the valve leaflets appear vortex-like in nature, these are essentially regions of flow stagnation [Images based on data from Wilson et al (Wilson et al, 2013)].…”