A utophagy is a complex intracellular process that delivers cytoplasmic constituents for degradation into lysosomes.1,2 Three main types of autophagy have been described: (1) microautophagy, comprising direct engulfment of cytoplasmic material by lysosomes via inward invaginations of the lysosomal membrane, (2) macroautophagy, characterized by formation of double-membrane sequestering compartments termed autophagosomes that fuse with lysosomes for delivery of cytoplasmic cargo, and (3) chaperone-mediated autophagy, mediated by a chaperone complex and lysosomal-associated membrane protein type 2A to degrade cytosolic proteins with a specific targeting motif. The term autophagy usually refers to macroautophagy, which is the most prevalent and beststudied form of autophagy. Also in this review, we will focus exclusively on macroautophagy, further cited as autophagy.Autophagy occurs at basal levels in most tissues to allow constitutive turnover of cytosolic components but is stimulated by environmental stress-related signals (eg, nutrient deprivation and oxidative injury) to recycle nutrients and to generate energy for maintenance of cell viability in unfavorable conditions.1 In addition to cellular stress, basal autophagy can be intensified by specific drugs, 3 indicating that the autophagic machinery is a potential therapeutic target for diverse diseases. Indeed, given that autophagy is involved in the prevention

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.

Spermidine inhibits lipid accumulation and necrotic core formation through stimulation of cholesterol efflux, albeit without changing plaque size or cellular composition. These effects, which are driven by autophagy in VSMCs, support the general idea that autophagy induction is potentially useful to prevent vascular disease.

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