Lymphatic remodelling in response to lymphatic injury in the hind limbs of sheep

Nelson, Tyler S.; Nepiyushchikh, Zhanna; Hooks, Joshua; Razavi, Mohammad; Lewis, Thomas A.; Clement, Cristina C.; Thoresen, Merrilee; Cribb, Matthew T.; Ross, Mindy K.; Gleason, Rudolph L.; Santambrogio, Laura; Peroni, John F.; Dixon, J. Brandon

doi:10.1038/s41551-019-0493-1

Cited by 10 publications

(18 citation statements)

References 69 publications

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“…What causes the functional changes in the intact collecting lymphatics possibly needs to be investigated by studying the molecular changes in the remodelled vessels. A recent study has shown that the collecting lymphatics in a contralateral lymphatic injury model in the hindlimb of sheep expressed markers of oxidative stress (Nelson et al 2020), which makes reactive oxygen species (ROS) promising candidates in investigating the ligation-induced remodelling of the collecting lymphatics. Since the remodelling happens in the context of OPW-induced entrainment, ROS should also be investigated as a molecular regulator of entrainment in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…All the data were collected in the form of the near-infrared fluorescence from an injected dye. The NIR dye used for this purpose was prepared by conjugating the commercially available IRDye 800 CW to 20 kDa polyethylene glycol (PEG) as described in previous literature (Nelson et al 2020). This enabled the dye to be taken up specifically by the lymphatics upon an intradermal injection.…”

Section: Data Acquisitionmentioning

confidence: 99%

“…It is known that lymphoedema causes abnormal lymphatic formation, manifesting as both abnormal lymphangiogenesis and/or remodelled collecting vessels (Mihara et al 2012). The short-term and long-term impact of aberrant mechanical loading on collecting lymphatic function have been investigated, and functional changes in the collecting lymphatics in response to a mechanical overload were observed (Olszewski, 2002(Olszewski, , 2008Modi et al 2007;Dongaonkar et al 2013;Gousopoulos et al 2016;Nelson et al 2020). However, changes in the mechanosensitivity of the lymphatic vessels during lymphoedema and, in turn, its impact on lymphatic transport function, are not well understood.…”

Section: Introductionmentioning

confidence: 99%

“…2016; Nelson et al . 2020). However, changes in the mechanosensitivity of the lymphatic vessels during lymphoedema and, in turn, its impact on lymphatic transport function, are not well understood.…”

Section: Introductionmentioning

confidence: 99%

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

Mukherjee

Nepiyushchikh

Michalaki

et al. 2021

The Journal of Physiology

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Data Acquisitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Mukherjee

Nepiyushchikh

Michalaki

et al. 2021

The Journal of Physiology

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“…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 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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Background and Objectives: Diabetes mellitus type 2 (T2DM) is a chronic disease associated with fluid accumulation in the interstitial tissue. Manual lymphatic drainage (MLD) plays a role in reducing lymphoedema, like intermittent pneumatic compression (IPC). By the present pilot study, we aimed to evaluate the efficacy of a synergistic treatment with MLD and IPC in reducing lower limb lymphedema in T2DM patients. Materials and Methods: Adults with a clinical diagnosis of T2DM and lower limb lymphedema (stage II–IV) were recruited from July to December 2020. Study participants were randomized into two groups: experimental group, undergoing a 1-month rehabilitative program consisting of MLD and IPC (with a compression of 60 to 80 mmHg); control group, undergoing MLD and a sham IPC (with compression of <30 mmHg). The primary outcome was the lower limb lymphedema reduction, assessed by the circumferential method (CM). Secondary outcomes were: passive range of motion (pROM) of hip, knee, and ankle; quality of life; laboratory exams as fasting plasma glucose and HbA1c. At baseline (T0) and at the end of the 1-month rehabilitative treatment (T1), all the outcome measures were assessed, except for the Hb1Ac evaluated after three months. Results: Out of 66 T2DM patients recruited, only 30 respected the eligibility criteria and were randomly allocated into 2 groups: experimental group (n = 15; mean age: 54.2 ± 4.9 years) and control group (n = 15; mean age: 54.0 ± 5.5 years). At the intra-group analysis, the experimental group showed a statistically significant improvement of all outcome measures (p < 0.05). The between-group analysis showed a statistically significant improvement in pROM of the hip, knee, ankle, EQ-VAS, and EQ5D3L index at T1. Conclusions: A multimodal approach consisting of IPC and MLD showed to play a role in reducing lower limb lymphedema, with an increase of pROM and HRQoL. Since these are preliminary data, further studies are needed.

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Mechanobiology of Lymphatic Vessels

Mukherjee

Dixon

2021

Vascular Mechanobiology in Physiology and Disease

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Lymphatic remodelling in response to lymphatic injury in the hind limbs of sheep

Cited by 10 publications

References 69 publications

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

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

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

Mechanobiology of Lymphatic Vessels

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