Defective autophagy in vascular smooth muscle cells alters contractility and Ca2+ homeostasis in mice

2015 ◽  
Vol 308 (6) ◽  
pp. H557-H567 ◽  
Author(s):  
Cédéric F. Michiels ◽  
Paul Fransen ◽  
Dorien G. De Munck ◽  
Guido R. Y. De Meyer ◽  
Wim Martinet
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Vascular Smooth Muscle ◽  
Vascular Reactivity ◽  
Contractile Function ◽  
Cell Types ◽  
Resting Membrane Potential ◽  
Plasmic Reticulum ◽  
Old Mice

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 Ca2+ mobilization and contraction remains poorly understood. Recent evidence shows that autophagy is involved in controlling contractile function and Ca2+ homeostasis in certain cell types. Therefore, autophagy might also regulate contractile capacity and Ca2+-mobilizing pathways in VSMCs. Contractility (organ chambers) and Ca2+ 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 Ca2+ 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 Ca2+-ATPase 2 expression and higher store-operated Ca2+ entry, promoted inositol 1,4,5-trisphosphate-mediated contractions of Atg7 fl/ fl SM22α -Cre+ segments and maximized the Ca2+ storing capacity of the sarcoplasmic reticulum. Moreover, decreased plasma membrane Ca2+-ATPase expression in Atg7 fl/ fl SM22α -Cre+ VSMCs hampered Ca2+ extrusion to the extracellular environment. Overall, our study indicates that defective autophagy in VSMCs leads to an imbalance between Ca2+ release/influx and Ca2+ reuptake/extrusion, resulting in higher basal Ca2+ concentrations and significant effects on vascular reactivity.

Role of Sarcoplasmic Reticulum in the Contractile Function of Vascular Smooth Muscle as Studied by 2,5-Di-(Tert-Butyl)-1,4-Benzohydroquinone

Neurosignals ◽  
1992 ◽  
Vol 1 (4) ◽  
pp. 182-193 ◽  
Author(s):  
Hiroyuki Shimamoto ◽  
Ingrid L.A. Majarais ◽  
Yoriko Shimamoto ◽  
Chiu-Yin Kwan ◽  
Edwin E. Daniel
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Vascular Smooth Muscle ◽  
Contractile Function ◽  
Tert Butyl

Regulation of Smooth Muscle Contraction by the Epithelium: Role of Prostaglandins

Physiology ◽  
2011 ◽  
Vol 26 (3) ◽  
pp. 156-170 ◽  
Author(s):  
Ye Chun Ruan ◽  
Wenliang Zhou ◽  
Hsiao Chang Chan
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Muscle Contraction ◽  
Cell Types ◽  
Smooth Muscle Contraction ◽  
Organ Systems ◽  
Wide Range ◽  
Important Regulator

As an analog to the endothelium situated next to the vascular smooth muscle, the epithelium is emerging as an important regulator of smooth muscle contraction in many vital organs/tissues by interacting with other cell types and releasing epithelium-derived factors, among which prostaglandins have been demonstrated to play a versatile role in governing smooth muscle contraction essential to the physiological and pathophysiological processes in a wide range of organ systems.

Prenyltransferase inhibitors block superoxide production by pulmonary vascular smooth muscle

2000 ◽  
Vol 278 (2) ◽  
pp. L329-L334 ◽  
Author(s):  
Ahmad Boota ◽  
Bruce Johnson ◽  
Kee-L Lee ◽  
Michelle A. Blaskovich ◽  
Shang-Xi Liu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Inflammatory Cytokine ◽  
Vascular Reactivity ◽  
Superoxide Production ◽  
Platelet Derived Growth Factor ◽  
Nitric Oxide Production ◽  
Farnesyltransferase Inhibitor ◽  
Superoxide Generation

We recently showed that the farnesyltransferase inhibitor FTI-277 blocks interleukin 1β (IL-1β)-induced nitric oxide production in pulmonary vascular smooth muscle cells (SMC), whereas the geranylgeranyltransferase inhibitor GGTI-298 enhances this effect. Here we show that IL-1β and platelet-derived growth factor (PDGF) stimulate superoxide production by pulmonary vascular SMC and that this effect is blocked by both FTI-277 and GGTI-298, suggesting that farnesylated and geranylgeranylated proteins are required for superoxide production. We also show that FTI-277 and GGTI-298 block superoxide production stimulated by constitutively active mutant H-Ras. Furthermore, superoxide production by IL-1β, PDGF factor, and constitutively activated Ras is blocked by diphenyleneiodonium, implicating NAD(P)H oxidase as the generating enzyme. Given the role of oxidant radicals in vascular reactivity and injury, the action of both FTI-277 and GGTI-298 in suppressing superoxide generation by an inflammatory cytokine as well as by a potent smooth muscle mitogen may be therapeutically useful.

scholarly journals The Role of Mechanotransduction on Vascular Smooth Muscle Myocytes Cytoskeleton and Contractile Function

2014 ◽  
Vol 297 (9) ◽  
pp. 1758-1769 ◽  
Author(s):  
George J.C. Ye ◽  
Alexander P. Nesmith ◽  
Kevin Kit Parker
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Contractile Function

Resting calcium influx in airway smooth muscle

2005 ◽  
Vol 83 (8-9) ◽  
pp. 717-723 ◽  
Author(s):  
Luis M Montaño ◽  
Blanca Bazán-Perkins
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Calcium Influx ◽  
Physiological Role ◽  
Resting Membrane Potential ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
Influx Pathways

Plasma membrane Ca2+ leak remains the most uncertain of the cellular Ca2+ regulation pathways. During passive Ca2+ influx in non-stimulated smooth muscle cells, basal activity of constitutive Ca2+ channels seems to be involved. In vascular smooth muscle, the 3 following Ca2+ entry pathways contribute to this phenomenon: (i) via voltage-dependent Ca2+ channels, (ii) receptor gated Ca2+ channels, and (iii) store operated Ca2+ channels, although, in airway smooth muscle it seems only 2 passive Ca2+ influx pathways are implicated, one sensitive to SKF 96365 (receptor gated Ca2+ channels) and the other to Ni2+ (store operated Ca2+ channels). Resting Ca2+ entry could provide a sufficient amount of Ca2+ and contribute to resting intracellular Ca2+ concentration ([Ca2+]i), maintenance of the resting membrane potential, myogenic tone, and sarcoplasmic reticulum-Ca2+ refilling. However, further research, especially in airway smooth muscle, is required to better explore the physiological role of this passive Ca2+ influx pathway as it could be involved in airway hyperresponsiveness.Key words: basal Ca2+ entry, constitutive Ca2+ channels, airway and vascular smooth muscle, SKF 96365, Ni2+.

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