Lymphatic injury alters the contractility and mechanosensitivity of collecting lymphatics to intermittent pneumatic compression

Abstract

Key points We present the first in vivo evidence that lymphatic contraction can entrain with an external oscillatory mechanical stimulus. Lymphatic injury can alter collecting lymphatic contractility, but not much is known about how its mechanosensitivity to external pressure is affected, which is crucial given the current pressure application methods for treating lymphoedema. We show that oscillatory pressure waves (OPW), akin to intermittent pneumatic compression (IPC) therapy, optimally entrain lymphatic contractility and modulate function depending on the frequency and propagation speed of the OPW. We show that the OPW‐induced entrainment and contractile function in the intact collecting lymphatics are enhanced 28 days after a contralateral lymphatic ligation surgery. The results show that IPC efficacy can be improved through proper selection of OPW parameters, and that collecting lymphatics adapt their function and mechanosensitivity after a contralateral injury, switching their behaviour to a pump‐like configuration that may be more suited to the altered microenvironment. Abstract Intermittent pneumatic compression (IPC) is commonly used to control the swelling due to lymphoedema, possibly modulating the collecting lymphatic function. Lymphoedema causes lymphatic contractile dysfunction, but the consequent alterations in the mechanosensitivity of lymphatics to IPC is not known. In the present work, the spatiotemporally varying oscillatory pressure waves (OPW) generated during IPC were simulated to study the modulation of lymphatic function by OPW under physiological and pathological conditions. OPW with three temporal frequencies and three propagation speeds were applied to rat tail collecting lymphatics. The entrainment of the lymphatics to OPW was significantly higher at a frequency of 0.05 Hz compared with 0.1 Hz and 0.2 Hz (P = 0.0054 and P = 0.014, respectively), but did not depend on the OPW propagation speed. Lymphatic function was significantly higher at a frequency of 0.05 Hz and propagation speed of 2.55 mm/s (P = 0.015). Exogenous nitric oxide was not found to alter OPW‐induced entrainment. A contralateral lymphatic ligation surgery was performed to simulate partial lymphatic injury in rat tails. The intact vessels showed a significant increase in entrainment to OPW, 28 days after ligation (compared with sham) (P = 0.016), with a similar increase in lymphatic transport function (P = 0.0029). The results suggest an enhanced mechanosensitivity of the lymphatics, along with a transition to a pump‐like behaviour, in response to a lymphatic injury. These results enhance our fundamental understanding of how lymphatic mechanosensitivity assists the coordination of lymphatic contractility and how this might be leveraged in IPC therapy.

Effects of Intermittent Pneumatic Compression on Lower Limb Lymphedema in Patients with Type 2 Diabetes Mellitus: A Pilot Randomized Controlled Trial

“…These tools consisted of single or double chambers with the same number of channels, with a worse compression adjustment. It is crucial to select the correct parameters for IPC that might enhance overall lymphatic transport by modulating the lymphatic contractility, considering that the increase in mechanosensitivity is an acute response to lymphatic injury, leading to an increase in the pump-like behavior of lymphatics [ 35 , 48 ]. Furthermore, the use of high pressures (>80 mmHg) favored excessive blood movement [ 49 ].…”

“…This tool could apply pressures between 0 and 300 mmHg pressure, but pressures between 30 and 60 mmHg were generally preferred. Mukherjee et al, in 2021, firstly provided evidence that the in vivo modulation of lymphatic contractility by external oscillatory pressure depends on the parameters of the stimulation [ 35 ]. Specifically, IPC modulates function depending on the oscillatory pressure wave frequency and propagation speed [ 35 , 36 ].…”

“…Mukherjee et al, in 2021, firstly provided evidence that the in vivo modulation of lymphatic contractility by external oscillatory pressure depends on the parameters of the stimulation [ 35 ]. Specifically, IPC modulates function depending on the oscillatory pressure wave frequency and propagation speed [ 35 , 36 ]. In rat models, the oscillatory shear stress induced a lymphangion contractility adaptation as a function of its intrinsic contractility and shear sensitivity [ 35 , 36 ].…”

“…Specifically, IPC modulates function depending on the oscillatory pressure wave frequency and propagation speed [ 35 , 36 ]. In rat models, the oscillatory shear stress induced a lymphangion contractility adaptation as a function of its intrinsic contractility and shear sensitivity [ 35 , 36 ].…”

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.…”