Characterization of rat tail lymphatic contractility and biomechanics: incorporating nitric oxide-mediated vasoregulation

Abstract

The lymphatic system transports lymph from the interstitial space back to the great veins via a series of orchestrated contractions of chains of lymphangions. Biomechanical models of lymph transport, validated with ex vivo or in vivo experimental results, have proved useful in revealing novel insight into lymphatic pumping; however, a need remains to characterize the contributions of vasoregulatory compounds in these modelling tools. Nitric oxide (NO) is a key mediator of lymphatic pumping. We quantified the active contractile and passive biaxial biomechanical response of rat tail collecting lymphatics and changes in the contractile response to the exogenous NO administration and integrated these findings into a biomechanical model. The passive mechanical response was characterized with a three-fibre family model. Nonlinear regression and non-parametric bootstrapping were used to identify best-fit material parameters to passive cylindrical biaxial mechanical data, assessing uniqueness and parameter confidence intervals; this model yielded a good fit ( R 2 = 0.90). Exogenous delivery of NO via sodium nitroprusside (SNP) elicited a dose-dependent suppression of contractions; the amplitude of contractions decreased by 30% and the contraction frequency decreased by 70%. Contractile function was characterized with a modified Rachev–Hayashi model, introducing a parameter that is related to SNP concentration; the model provided a good fit ( R 2 = 0.89) to changes in contractile responses to varying concentrations of SNP. These results demonstrated the significant role of NO in lymphatic pumping and provide a predictive biomechanical model to integrate the combined effect of mechanical loading and NO on lymphatic contractility and mechanical response.

A 1D Model Characterizing the Role of Spatiotemporal Contraction Distributions on Lymph Transport

“…Among these, adding initial lymphatic vessels and considering leakiness of the primary valves could provide a better picture of how lymphedema develops. Also, in this model the contractions are decoupled from the pressure and WSS effects, which is not the case in lymphatics 15,17,40,41,45,46 . So, to add another layer of complexity, one may add pressure/WWS and contraction couplings to include the mechanical effects.…”

“…Also, by using a correction factor proposed by Razavi et al . we can easily scale the pre- and peak-twitch curves to prescribe the mechanical response under disturbed chemical (nitric oxide) environment 45 . Finally, due to high energy loss at the valves in KO models, the model suggests to study the morphology of valve leaflets in lymphedema and how they possibly exacerbate the pumping efficiency.…”

Engineered models of the lymphatic vascular system: Past, present, and future

“…Mechano‐ and neurobiological mediators such as calcium (Ca 2+ ) and nitric oxide (NO) are shown as key mediators of lymphatic pumping 44 . Due to ease of isolation and straightforward cannulation procedure, rat tail ex vivo preparation has been widely used recently to study lymphatic contractility and substance‐mediated vasoregulation 45–48 . Razavi et al 45 quantified the passive and active biomechanical response of rat tail collecting lymphatics to NO perfusion by placing the vessel in a custom‐designed vessel chamber and then controlling the transmural pressure via a syringe pump connected to pressure sensors.…”

“…44 Due to ease of isolation and straightforward cannulation procedure, rat tail ex vivo preparation has been widely used recently to study lymphatic contractility and substance-mediated vasoregulation. [45][46][47][48] Razavi et al 45 quantified the passive and active biomechanical response of rat tail collecting lymphatics to NO perfusion by placing the vessel in a custom-designed vessel chamber and then controlling the transmural pressure via a syringe pump connected to pressure sensors. Their results showed the significant effect of NO in regulating lymphatic pumping and set a biomechanical model of lymphatic pumping with the integration of mechanical loading with NO pathway.…”

A multiscale sliding filament model of lymphatic muscle pumping

“…Computational research into lymphatic muscle has focused on the regulation of contractions and the electrical properties of lymphatic muscle (Baish et al 2016;Contarino & Toro 2018;Kunert et al 2015). While there have been multiple computer models phenomenologically incorporating both phasic and tonic contractions of lymphatic muscle (Caulk et al 2016;Caulk et al 2015;Kunert et al 2015;Razavi et al 2020;Razavi et al 2017), the different effects of the contraction types were the focus of only one series of computational modelling papers. This model used the time-varying elastance model of the heart combined with the transmission line equations for blood vessels (Quick et al 2008;Venugopal et al 2007;Venugopal et al 2010;Venugopal et al 2004;Venugopal et al 2003).…”