Lymphatic muscle cells are unique cells that undergo aging induced changes

Lei, Pin-Ji; Ruscic, Katarina J.; Roh, Kangsan; Rajotte, Johanna J.; O’Melia, Meghan J.; Bouta, Echoe M.; Marquez, Marla; Pereira, Ethel R.; Kumar, Ashwin S.; Arroyo-Ataz, Guillermo; Razavi, Mohammad S.; Zhou, Hengbo; Menzel, Lutz; Kumra, Heena; Duquette, Mark; Huang, Peigen; Baish, James W.; Munn, Lance L.; Ubellacker, Jessalyn M.; Jones, Dennis; Padera, Timothy P.

doi:10.1101/2023.11.18.567621

Cited by 4 publications

(2 citation statements)

References 149 publications

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“…To test whether our wavelet analysis can be applied to lymphatic contractility measurements from intravital epifluorescence microscopy, we re-analyzed previously published intravital epifluorescence microscopy data in young and old mice[33] that was previously quantified using only peak and valley analysis (Figure 4A). Both traditional peak-and-valley and wavelet analyses suggest there is no statistically significant difference in frequency between young and old mice (e.g., 8.3 ± 0.9 for young and 7.7 ± 0.9 for aged mice, based on peak-and-valley analysis).…”

Section: Resultsmentioning

confidence: 99%

A Multiresolution Approach with Method-Informed Statistical Analysis for Quantifying Lymphatic Pumping Dynamics

Razavi,

Ruscic,

Korn

et al. 2024

Preprint

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Despite significant strides in lymphatic system imaging, the timely diagnosis of lymphatic disorders remains elusive. One main cause for this is the absence of standardized, quantitative methods for real-time analysis of lymphatic contractility. Here, we address this unmet need by combining near-infrared lymphangiography imaging with an innovative analytical workflow. We combined data acquisition, signal processing, and statistical analysis to integrate traditional peak-and-valley with advanced wavelet time-frequency analyses. Decision theory was used to evaluate the primary drivers of attributable variance in lymphangiography measurements to generate a strategy for optimizing the number of repeat measurements needed per subject to increase measurement reliability. This approach not only offers detailed insights into lymphatic pumping behaviors across species, sex and age, but also significantly boosts the reliability of these measurements by incorporating multiple regions of interest and evaluating the lymphatic system under various gravitational loads. By addressing the critical need for improved imaging and quantification methods, our study offers a new standard approach for the imaging and analysis of lymphatic function that can improve our understanding, diagnosis, and treatment of lymphatic diseases. The results highlight the importance of comprehensive data acquisition strategies to fully capture the dynamic behavior of the lymphatic system.

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Section: Resultsmentioning

confidence: 99%

A Multiresolution Approach with Method-Informed Statistical Analysis for Quantifying Lymphatic Pumping Dynamics

Razavi,

Ruscic,

Korn

et al. 2024

Preprint

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“…In this study, we present one of the first single-cell RNA sequencing (scRNAseq) datasets generated from isolated lymphatic vessels 38 . Our study presents a controlled and spatially defined scRNAseq dataset that included collecting lymphatic vessels from multiple anatomical regions and compared both sexes.…”

Section: Introductionmentioning

confidence: 99%

TRPV4-Expressing Tissue-Resident Macrophages Regulate the Function of Collecting Lymphatic Vessels via Thromboxane A2 Receptors in Lymphatic Muscle Cells

Schulz,

Akerstrom,

Song

et al. 2024

Preprint

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Rationale: TRPV4 channels are critical regulators of blood vascular function and have been shown to be dysregulated in many disease conditions in association with inflammation and tissue fibrosis. These are key features in the pathophysiology of lymphatic system diseases, including lymphedema and lipedema; however, the role of TRPV4 channels in the lymphatic system remains largely unexplored. TRPV4 channels are calcium permeable, non-selective cation channels that are activated by diverse stimuli, including shear stress, stretch, temperature, and cell metabolites, which may regulate lymphatic contractile function. Objective: To characterize the expression of TRPV4 channels in collecting lymphatic vessels and to determine the extent to which these channels regulate the contractile function of lymphatics. Methods and Results: Pressure myography on intact, isolated, and cannulated lymphatic vessels showed that pharmacological activation of TRPV4 channels with GSK1016790A (GSK101) led to contractile dysregulation. The response to GSK101 was multiphasic and included, 1) initial robust constriction that was sustained for ≥1 minute and in some instances remained for ≥4 minutes; and 2) subsequent vasodilation and partial or complete inhibition of lymphatic contractions associated with release of nitric oxide. The functional response to activation of TRPV4 channels displayed differences across lymphatics from four anatomical regions, but these differences were consistent across different species (mouse, rat, and non-human primate). Importantly, similar responses were observed following activation of TRPV4 channels in arterioles. The initial and sustained constriction was prevented with the COX inhibitor, indomethacin. We generated a controlled and spatially defined single-cell RNA sequencing (scRNAseq) dataset from intact and microdissected collecting lymphatic vessels. Our data uncovered a subset of macrophages displaying the highest expression of Trpv4 compared to other cell types within and surrounding the lymphatic vessel wall. These macrophages displayed a transcriptomic profile consistent with that of tissue-resident macrophages (TRMs), including differential expression of Lyve1, Cd163, Folr2, Mrc1, Ccl8, Apoe, Cd209f, Cd209d, and Cd209g; and at least half of these macrophages also expressed Timd4. This subset of macrophages also highly expressed Txa2s, which encodes the thromboxane A2 (TXA2) synthase. Inhibition of TXA2 receptors (TXA2Rs) prevented TRPV4-mediated contractile dysregulation. TXA2R activation on LMCs caused an increase in mobilization of calcium from intracellular stores through Ip3 receptors which promoted store operated calcium entry and vasoconstriction. Conclusions: Clinical studies have linked cancer-related lymphedema with an increased infiltration of macrophages. While these macrophages have known anti-inflammatory and pro-lymphangiogenic roles, as well as promote tissue repair, our results point to detrimental effects to the pumping capacity of collecting lymphatic vessels mediated by activation of TRPV4 channels in macrophages. Pharmacological targeting of TRPV4 channels in LYVE1-expressing macrophages or pharmacological targeting of TXA2Rs may offer novel therapeutic strategies to improve lymphatic pumping function and lymph transport in lymphedema.

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Pacemaking in the lymphatic system

Davis,

Zawieja

2024

The Journal of Physiology

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Lymphatic collecting vessels exhibit spontaneous phasic contractions that are critical for lymph propulsion and tissue fluid homeostasis. This rhythmic activity is driven by action potentials conducted across the lymphatic muscle cell (LMC) layer to produce entrained contractions. The contraction frequency of a lymphatic collecting vessel displays exquisite mechanosensitivity, with a dynamic range from <1 to >20 contractions per minute. A myogenic pacemaker mechanism intrinsic to the LMCs was initially postulated to account for pressure‐dependent chronotropy. Further interrogation into the cellular constituents of the lymphatic vessel wall identified non‐muscle cell populations that shared some characteristics with interstitial cells of Cajal, which have pacemaker functions in the gastrointestinal and lower urinary tracts, thus raising the possibility of a non‐muscle cell pacemaker. However, recent genetic knockout studies in mice support LMCs and a myogenic origin of the pacemaker activity. LMCs exhibit stochastic, but pressure‐sensitive, sarcoplasmic reticulum calcium release (puffs and waves) from IP3R1 receptors, which couple to the calcium‐activated chloride channel Anoctamin 1, causing depolarisation. The resulting electrical activity integrates across the highly coupled lymphatic muscle electrical syncytia through connexin 45 to modulate diastolic depolarisation. However, multiple other cation channels may also contribute to the ionic pacemaking cycle. Upon reaching threshold, a voltage‐gated calcium channel‐dependent action potential fires, resulting in a nearly synchronous calcium global calcium flash within the LMC layer to drive an entrained contraction. This review summarizes the key ion channels potentially responsible for the pressure‐dependent chronotropy of lymphatic collecting vessels and various mechanisms of IP3R1 regulation that could contribute to frequency tuning. image

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Lymphatic muscle cells are unique cells that undergo aging induced changes

Cited by 4 publications

References 149 publications

A Multiresolution Approach with Method-Informed Statistical Analysis for Quantifying Lymphatic Pumping Dynamics

A Multiresolution Approach with Method-Informed Statistical Analysis for Quantifying Lymphatic Pumping Dynamics

TRPV4-Expressing Tissue-Resident Macrophages Regulate the Function of Collecting Lymphatic Vessels via Thromboxane A2 Receptors in Lymphatic Muscle Cells

Pacemaking in the lymphatic system

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