Physiologic Properties and Regulation of the Actin Cytoskeleton in Vascular Smooth Muscle

Tang, Dale D.; Anfinogenova, Yana

doi:10.1177/1074248407313737

Cited by 92 publications

(155 citation statements)

References 134 publications

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“…A unique feature of tension development in smooth muscle cells is that the independently regulated contractile domain and cytoskeletal domains need to collaborate to produce force. This view is supported by numerous studies showing that in response to stimulation, the amount of F-actin in the cell increases, and if this new actin polymerization is blocked, tension is not developed (reviewed in 12, [18][19][20]. The mechanism by which actin polymerization facilitates force production may include an enhancement of the linkage of the actin filaments to integrins, which would strengthen force transduction between the contractile domain and the ECM.…”

Section: Discussionmentioning

confidence: 49%

Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin

Fagnant

Bookwalter

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Point mutations in vascular smooth muscle α-actin (SM α-actin), encoded by the gene ACTA2, are the most prevalent cause of familial thoracic aortic aneurysms and dissections (TAAD). Here, we provide the first molecular characterization, to our knowledge, of the effect of the R258C mutation in SM α-actin, expressed with the baculovirus system. Smooth muscles are unique in that force generation requires both interaction of stable actin filaments with myosin and polymerization of actin in the subcortical region. Both aspects of R258C function therefore need investigation. Total internal reflection fluorescence (TIRF) microscopy was used to quantify the growth of single actin filaments as a function of time. R258C filaments are less stable than WT and more susceptible to severing by cofilin. Smooth muscle tropomyosin offers little protection from cofilin cleavage, unlike its effect on WT actin. Unexpectedly, profilin binds tighter to the R258C monomer, which will increase the pool of globular actin (G-actin). In an in vitro motility assay, smooth muscle myosin moves R258C filaments more slowly than WT, and the slowing is exacerbated by smooth muscle tropomyosin. Under loaded conditions, small ensembles of myosin are unable to produce force on R258C actin-tropomyosin filaments, suggesting that tropomyosin occupies an inhibitory position on actin. Many of the observed defects cannot be explained by a direct interaction with the mutated residue, and thus the mutation allosterically affects multiple regions of the monomer. Our results align with the hypothesis that defective contractile function contributes to the pathogenesis of TAAD.actin | myosin II | smooth muscle | thoracic aortic aneurysms | vascular disease T horacic aortic aneurysms and dissections (TAAD) are the 18th most common cause of death in individuals in the United States (1). The high degree of mortality is partly due to the fact that aneurysms tend to be asymptomatic until a lifethreatening acute aortic dissection occurs. Familial TAAD is an autosomal dominant disorder with variable penetrance, which is characterized by enlargement or dissection of the thoracic aorta (reviewed in 2). The most prevalent genetic cause of familial TAAD, responsible for ∼15% of all cases, are mutations in vascular smooth muscle α-actin (SM α-actin), encoded by the gene ACTA2. More than 40 mutations in ACTA2 have been identified to date (3-5). Intriguingly, ACTA2 mutations also differentially predispose individuals to occlusive vascular diseases, such as premature coronary artery disease and strokes (6). ACTA2 mutations thus can lead to either dilation of large elastic arteries like the aorta or occlusion of smaller muscular arteries.SM α-actin is the most abundant protein in vascular smooth muscle cells, constituting ∼40% of the total protein and ∼70% of the total actin, with the rest composed of β-and γ-cytoplasmic actin. Actin is critical for contraction and force production by smooth muscle cells, as well as for their proliferation and migration. Dissected aortas show s...

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Section: Discussionmentioning

confidence: 49%

Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin

Fagnant

Bookwalter

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…As described above, Pfn-1 is an actin-regulatory protein that is capable of modulating actin dynamics and force development in smooth muscle in response to contractile stimulation (7,12,45). However, the mechanisms that regulate Pfn-1 are not well understood.…”

Section: Discussionmentioning

confidence: 99%

“…Pfn-1 has been implicated in promoting actin polymerization in vitro (9) and migration/proliferation of nonmuscle cells (10). Pfn-1 promotes actin polymerization by catalyzing the exchange of actinbound ADP for ATP and by releasing actin monomer from thymosin-␤4; both processes facilitate unidirectional addition of G-actin to F-actin (7,8,11). In smooth muscle, down-regulation of Pfn-1 inhibits actin polymerization and contractile force without affecting myosin light chain phosphorylation (12).…”

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confidence: 99%

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The Association of Cortactin with Profilin-1 Is Critical for Smooth Muscle Contraction

Wang

Cleary

Wang

et al. 2014

Journal of Biological Chemistry

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Background: Profilin-1 (Pfn-1) regulates actin dynamics and contraction in smooth muscle. Results: Contractile activation increases the association of cortactin with Pfn-1 via c-Abl, which controls actin dynamics and contraction. Conclusion:The coupling of cortactin with Pfn-1 regulated by c-Abl is critical for actin polymerization and contraction. Significance: The c-Abl-mediated cortactin/Pfn-1 interaction is a novel mechanism for the regulation of smooth muscle contraction.

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“…There are several possible mechanisms by which imatinib may elicit pulmonary vasodilation. These include: (1) inhibition of PDGF receptor-mediated elevation of the intracellular Ca 2+ levels (9); (2) inhibition of other offtarget protein kinases, such as epidermal growth factor receptor, Src and protein kinase C (10-12); and (3) inhibition of c-Abl-mediated actin polymerization (13).…”

Section: Discussionmentioning

confidence: 99%

Imatinib is Partially Effective for the Treatment of Pulmonary Capillary Hemangiomatosis

et al. 2014

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A 43-year-old man presented with dyspnea on exertion. Right heart catheterization demonstrated pulmonary arterial hypertension (PAH). He was treated with bosentan, sildenafil and intravenous epoprostenol. Despite the administration of such intensive therapy, the patient's condition deteriorated to a World Health Organization functional class (WHO-FC) of IV. He participated in a clinical trial of imatinib for PAH. After three months of treatment with imatinib, the chest X-ray and echocardiography findings improved, and the WHO-FC class was III. One year after, however, the PAH worsened again, and the patient died 2.6 years after the first diagnosis. At autopsy, patchy capillary proliferation was observed in the lungs. The definitive diagnosis was pulmonary capillary hemangiomatosis.

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Physiologic Properties and Regulation of the Actin Cytoskeleton in Vascular Smooth Muscle

Cited by 92 publications

References 134 publications

Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin

Vascular disease-causing mutation R258C in ACTA2 disrupts actin dynamics and interaction with myosin

The Association of Cortactin with Profilin-1 Is Critical for Smooth Muscle Contraction

Imatinib is Partially Effective for the Treatment of Pulmonary Capillary Hemangiomatosis

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