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

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 lymphedema. 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 functional 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 lymphatic adapt their function and mechanosensitivity after a contralateral injury, switching their behavior 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 lymphedema, possibly modulating the collecting lymphatic function. Lymphedema 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 to 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 to 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 behavior, 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. This article is protected by copyright. All rights reserved.