Scleraxis Alters Arterial Smooth Muscle Phenotypic Switching and Exacerbates Arterial Stiffness
Notice bibliographique
Résumé
Arterial stiffness (AS) is an impairment in arterial relaxation and function in blood pressure regulation and is associated with the development of multiple cardiovascular diseases including hypertension, atherosclerosis, and adverse outcomes such as stroke, heart failure, and death. AS comprises an increase in vascular wall components (extracellular matrix proteins or vascular smooth muscle cell (VSMC) composition) or cellular malfunction, or a combination of these factors. Preliminary data from our lab showed that using the Transverse Aortic Constriction (TAC) model, the transcription factor scleraxis is upregulated in the aortic wall on the pre-TAC/high pressure side versus post-TAC/low pressure side. Scleraxis also induces cellular phenotype activation of fibroblasts to myofibroblasts in cardiac fibrosis and mediates epithelial to mesenchymal transition in development. Angiotensin II (AngII) induces hypertension and increases stiffness in arteries, and we found that it also up-regulates scleraxis expression, suggesting the possibility that scleraxis may alter arterial wall composition. In this study, we investigated the role of scleraxis expression in VSMC, and its effect when over-expressed along with AngII treatment in small resistance arteries and aorta. In vivo, we upregulated scleraxis in VSMC using a Cre/LoxP approach and the tamoxifen-inducible Myh11cre mouse, with or without AngII delivery by micro-osmotic pump, then isolated 3rd order mesenteric arteries and assessed arterial function and stiffness by pressure myography. We harvested aortas for immunohistology staining and gene expression analysis. In vitro, we upregulated scleraxis in VSMC with or without AngII treatment and measured their proliferation by flow cytometry. Our findings show that scleraxis induces stiffness in mesenteric arteries, but not aorta by induction of VSMC proliferation. Scleraxis upregulation with AngII infusion exacerbates vascular stiffness in mesenteric arteries due to significant changes in arterial wall components, reducing internal lumen diameter and smooth muscle relaxation. At the molecular level, extracellular matrix protein expression is reduced in aortas. In in vitro studies, scleraxis-AngII treated VSMC exhibit lower proliferative capacity, distinct morphological changes and higher contractile gene expression, indicative of a hypertrophic contractile phenotype altering overall arterial stiffness. Our study shows that scleraxis alone can induce AS by regulating VSMC phenotype toward proliferation. In contrast, arterial stiffness is exacerbated in scleraxis overexpression and AngII-infused vessels by inducing VSMC towards a hypertrophic contractile phenotype. Therefore, scleraxis alters vascular smooth muscle phenotypic switching and arterial stiffness through different mechanisms, depending on the presence of AngII, which may have different pathological impacts depending on the specific underlying conditions. This work is supported by funding from Heart & Stroke Foundation and BMO Studentship. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Prédiction distillée sur la base complète
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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 | 0,000 | 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 | 0,001 |
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.
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