Details

Autor(en) / Beteiligte

• Michiels, Cédéric F.
• Fransen, Paul
• De Munck, Dorien G.
• De Meyer, Guido R. Y.
• Martinet, Wim

Titel

Defective autophagy in vascular smooth muscle cells alters contractility and Ca 2+ homeostasis in mice

Ist Teil von

• American journal of physiology. Heart and circulatory physiology, 2015-03, Vol.308 (6), p.H557-H567

Erscheinungsjahr

2015

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• Autophagy is an evolutionary preserved process that prevents the accumulation of unwanted cytosolic material through the formation of autophagosomes. Although autophagy has been extensively studied to understand its function in normal physiology, the role of vascular smooth muscle (SM) cell (VSMC) autophagy in Ca 2+ mobilization and contraction remains poorly understood. Recent evidence shows that autophagy is involved in controlling contractile function and Ca 2+ homeostasis in certain cell types. Therefore, autophagy might also regulate contractile capacity and Ca 2+ -mobilizing pathways in VSMCs. Contractility (organ chambers) and Ca 2+ homeostasis (myograph) were investigated in aortic segments of 3.5-mo-old mice containing a SM cell-specific deletion of autophagy-related 7 ( Atg7; Atg7 fl/ fl SM22α -Cre + mice) and in segments of corresponding control mice ( Atg7 +/+ SM22α -Cre + ). Our results indicate that voltage-gated Ca 2+ channels (VGCCs) of Atg7 fl/ fl SM22α -Cre + VSMCs were more sensitive to depolarization, independent of changes in resting membrane potential. Contractions elicited with K + (50 mM) or the VGCC agonist BAY K8644 (100 nM) were significantly higher due to increased VGCC expression and activity. Interestingly, the sarcoplasmic reticulum of Atg7 fl/ fl SM22α -Cre + VSMCs was enlarged, which, combined with increased sarco(endo)plasmic reticulum Ca 2+ -ATPase 2 expression and higher store-operated Ca 2+ entry, promoted inositol 1,4,5-trisphosphate-mediated contractions of Atg7 fl/ fl SM22α -Cre + segments and maximized the Ca 2+ storing capacity of the sarcoplasmic reticulum. Moreover, decreased plasma membrane Ca 2+ -ATPase expression in Atg7 fl/ fl SM22α -Cre + VSMCs hampered Ca 2+ extrusion to the extracellular environment. Overall, our study indicates that defective autophagy in VSMCs leads to an imbalance between Ca 2+ release/influx and Ca 2+ reuptake/extrusion, resulting in higher basal Ca 2+ concentrations and significant effects on vascular reactivity.