Calcium dynamics and related alterations in pulmonary hypertension associated with heart failure
Notice bibliographique
Résumé
Congestive heart failure (CHF) represents an important Canadian health problem. Most patients with CHF develop pulmonary hypertension (PH), which is an important marker that signals progression of the disease and its poor outcome. Significant advances have been made for the treatment of heart failure (HF). Nevertheless, the morbidity and mortality among patients with advanced heart HF, who have developed PH remains high. Increased pulmonary vascular pressure (PVP) observed in PH leads to increased vascular tone and vascular remodelling associated with altered vasodilatory responses. It is noteworthy that a decrease in vasodilatory responses has been observed in PH. At the core of vasodilatory alterations lies endothelial dysfunction. This hallmark of most cardiovascular diseases is associated with alterations in calcium (Ca2+) homeostasis. Although global Ca2+ plays a role in a wide range of cellular functions, this thesis work focused on the impact of local Ca2+ signalling in endothelial cells (ECs). Among the different types of local Ca2+ signals, Ca2+ pulsars were identified. Ca2+ pulsars are local endothelial Ca2+ signals whose activity is finely regulated by physiological agents that modulate intracellular levels of inositol 1,4,5-triphosphate (IP3) and Ca2+. Ca2+ pulsars have been shown to have an effect on several important cellular functions. In mesenteric arteries, Ca2+ pulsars induce endotheliuminduced relaxation of vascular smooth muscle cells. Up until now, the regulatory mechanisms of Ca2+ pulsars remain to be uncovered. The spatio-temporal characteristics of Ca2+ pulsars suggest that they could play a role in the control of pulmonary vascular tone, potentially involving more transmembrane ion channels, as well as regulatory proteins. Transient receptor potential vanilloid 4 (TRPV4) channels are non-selective mechanosensitive osmo-regulated cation channels broadly expressed in a number of tissues. Activation of TRPV4 channels allows Ca2+ entry into the cell. A number of studies have shown the implication of TRPV4 as well as other channels from the TRP family in PH. Endothelial Ca2+-related pathophysiological mechanisms modulating pulmonary vascular tone and leading to the development of group II PH are poorly defined. In addition, the scarcity of studies exploring the pathophysiology and therapies of group II PH resides in the lack of validated small animal models with an adequate determination of the presence and severity of PH. The work in this thesis identified and characterized for the first time intracellular Ca2+ pulsars in pulmonary endothelium and their alterations in a clinically relevant mouse model of group II PH that was developed. In addition, this work revealed the implication of endothelial TRPV4 channels in Ca2+ pulsars dysregulation in group II-PH.
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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 | 0,000 | 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 | 0,001 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| 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 ».