Distinct roles of L‐ and T‐type voltage‐dependent Ca<sup>2+</sup>channels in regulation of lymphatic vessel contractile activity
Bibliographic record
Abstract
Key points Lymph transport is promoted by lymphatic pumping, a robust phasic contractile activity of the collecting lymphatic vessels. This contractile function, critical for tissue fluid homeostasis and immune cell transport to lymph nodes, is regulated by the amount of lymph entering the vessels and subsequent distension of the vessel wall. While lymphatic pumping relies on influx of Ca 2+ through voltage‐dependent Ca 2+ channels, characterization of these channels and details of their contribution to the regulation of stretch‐activated contractions are lacking. Here we report the expression of L‐ and T‐type Ca 2+ channels in rat mesenteric lymphatic vessels and their differential role in regulating strength and frequency of lymphatic contractions. This study fosters our knowledge on the mechanisms that drive stretch‐activated lymphatic contractions. It may help in providing a basis to developing agents able to enhance lymphatic function, which could be of therapeutic benefit during lymphatic impairment such as lymphoedema. Abstract Lymph drainage maintains tissue fluid homeostasis and facilitates immune response. It is promoted by phasic contractions of collecting lymphatic vessels through which lymph is propelled back into the blood circulation. This rhythmic contractile activity (i.e. lymphatic pumping) increases in rate with increase in luminal pressure and relies on activation of nifedipine‐sensitive voltage‐dependent Ca 2+ channels (VDCCs). Despite their importance, these channels have not been characterized in lymphatic vessels. We used pressure‐ and wire‐myography as well as intracellular microelectrode electrophysiology to characterize the pharmacological and electrophysiological properties of L‐type and T‐type VDCCs in rat mesenteric lymphatic vessels and evaluated their particular role in the regulation of lymphatic pumping by stretch. We complemented our study with PCR and confocal immunofluorescence imaging to investigate the expression and localization of these channels in lymphatic vessels. Our data suggest a delineating role of VDCCs in stretch‐induced lymphatic vessel contractions, as the stretch‐induced increase in force of lymphatic vessel contractions was significantly attenuated in the presence of L‐type VDCC blockers nifedipine and diltiazem, while the stretch‐induced increase in contraction frequency was significantly decreased by the T‐type VDCC blockers mibefradil and nickel. The latter effect was correlated with a hyperpolarization. We propose that activation of T‐type VDCCs depolarizes membrane potential, regulating the frequency of lymphatic contractions via opening of L‐type VDCCs, which drive the strength of contractions.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".