The Regulation of Lymphatic Muscle Cell Contractile Activity by Intracellular Calcium Signals
Notice bibliographique
Résumé
Lymphedema is characterized by chronic edema due to lymphatic insufficiency. Normally, the spontaneous contractions of the collecting lymphatic vessels (cLVs) function to pump lymph against a pressure gradient back to the blood stream, however cLVs from lymphedema patients often display weak or irregular pumping activity. We have recently shown that that mouse lymphatic muscle cells (LMCs) exhibit a diastolic depolarization that sets contraction frequency and is the basis of cLV pacemaking and autorhythmicity. In murine cLVs, this diastolic depolarization is pressure‐dependent and is mediated by the Ca 2+ activated chloride channel Anoctamin1 (Ano1). Ano1 is presumed to be activated by the spontaneous Ca 2+ transients originating from the sarcoplasmic reticulum (SR), however the identity of the SR Ca 2+ channels underlying these diastolic Ca 2+ transients has not been rigorously tested using genetic models. We tested the hypothesis that intracellular Ca 2+ signals released from the SR are critical in regulating lymphatic pacemaking and contractile activity. We sorted murine LMCs and observed expression of both Itpr1 and RyR2. We tested the role of Itpr1 and RyR2 in the electrical and contractile regulation of the murine inguinal‐axillary cLV (Ing‐Ax) through the use of inducible deletion models (MYH11CreERT2) or mice harboring knock‐in gain of function (GOF) of loss of function (LOF) mutations. These mouse models include Ano1 fl/fl , Itpr1 fl/fl , Itpr1 DK (GOF mutant), Itpr1 DA (LOF mutant), RyR2 fl/fl , and RyR2 VF (GOF mutant). We performed ex vivo isobaric vessel myography in response to a physiological pressure range to determine Ing‐Ax contraction frequency (Freq), contraction amplitude (Amp), and vessel tone (Tone). In some experiments, we also recorded membrane potential using “sharp electrodes” and imaged Ca 2+ signals using the genetically encoded cytosolic Ca 2+ sensor GCaMP6f or GCaMP8 from pressurized Ing‐Ax cLVs. Ing‐Ax cLVs isolated from the heterozygous Itpr1 DA/WT , the homozygous Itpr1 DA/DA , and Itpr1smKO mice had significantly reduced contraction Freq and Tone, but also observed significantly higher Amp. Strikingly, Itpr1smKO Ing‐Ax cLVs also lacked the pressure‐dependent chronotropy similar to cLVs from Ano1smKO mice, however Itpr1smKO vessels had unstable periodicity in the contraction rhythm. Ing‐Ax cLVs from RyR2smKO mice had normal contraction Freq, Amp and Tone. In contrast, Ing‐Ax cLVs from the GOF RyR2 VF/KO mice had significantly higher Tone and Freq, but significantly reduced Amp. Ing‐Ax cLVs from GOF Iptr1 DK mice contracted into a paralytic rigor during the vessel warming and equilibration period likely due to Ca 2+ overload. These findings suggest that the pressure‐dependent Freq in murine cLVs is mediated by the activation of Ano1 by SR Ca 2+ release through Itpr1 and an acceleration of the diastolic depolarization. Support or Funding Information R01‐H122578 (MD), R01‐HL133256 & R01‐HL137745 (JJ) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».