Distinct Effects of Voltage- and Store-dependent Calcium Influx on Stretch-induced Differentiation and Growth in Vascular Smooth Muscle

Abnormal vascular smooth muscle cell (VSMC) proliferation contributes to occlusive and proliferative disorders of the vessel wall. Salicylate and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit VSMC proliferation by an unknown mechanism unrelated to anti-inflammatory activity. In search for this mechanism, we have studied the effects of salicylate and other Increased vascular smooth muscle cell (VSMC) 3 proliferation, a process controlled by Ca 2ϩ channel switching, is a key event in the development of atherosclerosis, restenosis, and other occlusive and proliferative disorders of the vasculature (1, 2). Salicylate, the major aspirin metabolite, and other nonsteroidal anti-inflammatory drugs (NSAIDs) may induce direct, platelet-independent effects on the vascular wall (3-5). For example, salicylate effectively inhibits VSMC proliferation and DNA synthesis in vivo and in vitro without inducing cellular toxicity or apoptosis (4).A series of NSAIDs, including aspirin, ibuprofen, indomethacin, and sulindac, induce a dose-dependent inhibition of proliferation in A10 cells (6, 7), a VSMC cell line derived from embryonic rat aorta. The effects of NSAIDs occur in the absence of cytotoxicity and are independent of cyclooxygenase (7). Aspirin treatment also inhibits neointimal proliferation in dogs fed a cholesterol-enriched diet (8) and prevents the development of atherosclerosis in rabbits (9). Therefore, NSAIDs inhibit VSMC proliferation and show salutary effects in the treatment of vascular proliferative disorders by a yet unknown mechanism of action unrelated to anti-inflammatory activity.Intracellular Ca 2ϩ is a major trigger for vasoconstriction and a stimulus for VSMC proliferation (1, 2, 10). Several Ca 2ϩ channels participate in regulating intracellular Ca 2ϩ , including voltage-operated and store-operated Ca 2ϩ channels (10, 11). SOCE is activated after the emptying of intracellular Ca 2ϩ stores by physiological stimuli and is involved in cell proliferation in several cell types, including T cells (12,13). In these cells, SOCE requires not only the activating signal from the empty store but also the close proximity of functional mitochondria acting as Ca 2ϩ sinks to prevent the strong Ca 2ϩ -dependent inactivation of SOC channels (14 -18

Section: Discussionsupporting

confidence: 74%

Nonsteroidal Anti-inflammatory Drugs Inhibit Vascular Smooth Muscle Cell Proliferation by Enabling the Ca2+-dependent Inactivation of Calcium Release-activated Calcium/Orai Channels Normally Prevented by Mitochondria

Muñoz

Valero

Quintana

et al. 2011

“…cium influx via L-type calcium channels is an important regulator of Rho activity and expression of contractile smooth muscle markers (39,40). We therefore analyzed calcium levels in cells under high and low glucose conditions and found that baseline fluorescence of the Fluo-4 calcium indicator was significantly increased in cells subjected to hyperglycemia (Fig.…”

Section: Calcium Influx Via L-type Calcium Channels Is Involved In Thmentioning

confidence: 99%

Elevated Glucose Levels Promote Contractile and Cytoskeletal Gene Expression in Vascular Smooth Muscle via Rho/Protein Kinase C and Actin Polymerization

Hien¹,

Turczyńska²,

Dahan³

et al. 2016

Self Cite

Both type 1 and type 2 diabetes are associated with increased risk of cardiovascular disease. This is in part attributed to the effects of hyperglycemia on vascular endothelial and smooth muscle cells, but the underlying mechanisms are not fully understood. In diabetic animal models, hyperglycemia results in hypercontractility of vascular smooth muscle possibly due to increased activation of Rho-kinase. The aim of the present study was to investigate the regulation of contractile smooth muscle markers by glucose and to determine the signaling pathways that are activated by hyperglycemia in smooth muscle cells. Microarray, quantitative PCR, and Western blot analyses revealed that both mRNA and protein expression of contractile smooth muscle markers were increased in isolated smooth muscle cells cultured under high compared with low glucose conditions. This effect was also observed in hyperglycemic Akita mice and in diabetic patients. Elevated glucose activated the protein kinase C and Rho/Rho-kinase signaling pathways and stimulated actin polymerization. Glucose-induced expression of contractile smooth muscle markers in cultured cells could be partially or completely repressed by inhibitors of advanced glycation end products, L-type calcium channels, protein kinase C, Rho-kinase, actin polymerization, and myocardin-related transcription factors. Furthermore, genetic ablation of the miR-143/145 cluster prevented the effects of glucose on smooth muscle marker expression. In conclusion, these data demonstrate a possible link between hyperglycemia and vascular disease states associated with smooth muscle contractility.Diabetes confers a 2-4-fold excess risk for a wide range of cardiovascular diseases, including macrovascular complications leading to coronary heart disease and ischemic stroke, as well as microvascular diseases, such as nephropathy and retinopathy (1, 2). Based on current trends, the rising incidence of diabetes (expected to reach 333 million people worldwide by 2025) will undoubtedly equate to increased cardiovascular mortality. Chronic hyperglycemia has long been recognized as an independent risk factor for cardiovascular disease (3, 4). Importantly, the progressive relationship between glucose levels and cardiovascular risk extends below the threshold for diabetes diagnosis (fasting plasma glucose Ն7.0 mmol/liter or 2-h plasma glucose Ն11.1 mmol/liter (2, 3)), and more recently, even transient hyper-and hypoglycemia have emerged as important determinants of cardiovascular disease (5). Despite the vast clinical and epidemiological experience linking blood glucose and poor glucose control to the development and progression of cardiovascular disease, the underlying molecular mechanisms leading to vascular dysfunction and disease are poorly understood (6).It has been well established that hyperglycemia results in vascular hyperreactivity in diabetic patients (7) and animal models (8 -10). Part of this effect may be attributed to a decrease in nitric oxide (NO) bioavailability as well as a reduced respon...

“…Actin polymerization is known to regulate smooth muscle differentiation by promoting nuclear translocation of myocardin-related transcription factor, a transcriptional co-activator to serum response factor, which then induces transcription of smooth muscle-specific genes (11). Additionally, activation of the Rho signaling pathway may promote myocardin expression and smooth musclespecific gene transcription via the transcription factor Mef2 (12,13). Because multiple factors can induce Rho/Rho kinase activation, it has been a challenge to dissect those that play a role in stretch-induced smooth muscle differentiation.…”

mentioning

confidence: 99%

MicroRNAs Are Essential for Stretch-induced Vascular Smooth Muscle Contractile Differentiation via MicroRNA (miR)-145-dependent Expression of L-type Calcium Channels

Turczyńska

Sadegh

Hellstrand

et al. 2012

Self Cite

Background: miRNAs regulate smooth muscle phenotype. Results: Deletion of miRNAs results in impaired stretch induction of contractile differentiation and reduced expression of L-type calcium channels. Conclusion: miRNAs are crucial for stretch-sensitive smooth muscle differentiation in part via miR-145-dependent expression of L-type calcium channels. Significance: These findings provide novel insights into the mechanism of smooth muscle phenotypic modulation in vascular disease.