ACTA2

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Christina L Papke - One of the best experts on this subject based on the ideXlab platform.

  • loss of smooth muscle α actin leads to nf κb dependent increased sensitivity to angiotensin ii in smooth muscle cells and aortic enlargement
    Circulation Research, 2017
    Co-Authors: Jiyuan Chen, Andrew M Peters, Christina L Papke, Carlos Villamizar, Lea Jeanne Ringuette, Jiumei Cao, Shanzhi Wang, Limin Gong, Katerina L Byanova, Jian Xiong
    Abstract:

    Rationale: Mutations in ACTA2 , encoding the smooth muscle isoform of α-actin, cause thoracic aortic aneurysms, acute aortic dissections, and occlusive vascular diseases. Objective: We sought to identify the mechanism by which loss of smooth muscle α-actin causes aortic disease. Methods and Results: ACTA2 −/− mice have an increased number of elastic lamellae in the ascending aorta and progressive aortic root dilation as assessed by echocardiography that can be attenuated by treatment with losartan, an angiotensin II (AngII) type 1 receptor blocker. AngII levels are not increased in ACTA2 −/− aortas or kidneys. Aortic tissue and explanted smooth muscle cells from ACTA2 −/− aortas show increased production of reactive oxygen species and increased basal nuclear factor κB signaling, leading to an increase in the expression of the AngII receptor type I a and activation of signaling at 100-fold lower levels of AngII in the mutant compared with wild-type cells. Furthermore, disruption of smooth muscle α-actin filaments in wild-type smooth muscle cells by various mechanisms activates nuclear factor κB signaling and increases expression of AngII receptor type I a. Conclusions: These findings reveal that disruption of smooth muscle α-actin filaments in smooth muscle cells increases reactive oxygen species levels, activates nuclear factor κB signaling, and increases AngII receptor type I a expression, thus potentiating AngII signaling in vascular smooth muscle cells without an increase in the exogenous levels of AngII.

  • abstract 458 loss of smooth muscle α actin in mice results in thoracic aortic aneurysms via increased reactive oxygen species increased nox4 and increased angiotensin ii type 1 receptor mediated signaling
    Arteriosclerosis Thrombosis and Vascular Biology, 2015
    Co-Authors: Jiyuan Chen, Callie Kwartler, Christina L Papke, Carlos Villamizar, Lea Jeanne Ringuette, Jiumei Cao, Shanzhi Wang, Katerina L Byanova, Andrew Peters, Rosalinda Madonna
    Abstract:

    Objective: ACTA2 mutations cause 10-14% of familial thoracic aortic aneurysms and dissections. Mice deficient in smooth muscle α-actin (ACTA2-/-) develop root and ascending thoracic aortic enlargement associated with thickening of the aortic media and fragmentation and disarray of elastic fibers. We hypothesized that blocking AT1 activation would block the aortic pathology and prevent aortic enlargement in ACTA2-/- mice. Methods and Results: Beginning at 4 weeks of age, ACTA2-/- mice were treated with losartan or placebo (n≥10) for 6 months and echocardiograms were performed at baseline and every other month. The aortic root in ACTA2-/- mice was found to undergo progressive dilatation. After 6 months of treatment, there was no difference in the diameter of the aortic root between wild-type (WT) mice and the losartan treated mice (p=0.44). Histologic analysis of ACTA2-/- aortas demonstrated medial thickening and fragmentation of elastic fibers which was normalized by treatment with losartan. Gene expressio...

  • smooth muscle hyperplasia due to loss of smooth muscle α actin is driven by activation of focal adhesion kinase altered p53 localization and increased levels of platelet derived growth factor receptor β
    Human Molecular Genetics, 2013
    Co-Authors: Christina L Papke, Callie Kwartler, Carlos Villamizar, Jiumei Cao, Katerina L Byanova, Soonmi Lim, Harini Sreenivasappa, Grant M Fischer, John Pham, Meredith L Rees
    Abstract:

    Mutations in ACTA2, encoding the smooth muscle cell (SMC)-specific isoform of α-actin (α-SMA), cause thoracic aortic aneurysms and dissections and occlusive vascular diseases, including early onset coronary artery disease and stroke. We have shown that occlusive arterial lesions in patients with heterozygous ACTA2 missense mutations show increased numbers of medial or neointimal SMCs. The contribution of SMC hyperplasia to these vascular diseases and the pathways responsible for linking disruption of α-SMA filaments to hyperplasia are unknown. Here, we show that the loss of ACTA2 in mice recapitulates the SMC hyperplasia observed in ACTA2 mutant SMCs and determine the cellular pathways responsible for SMC hyperplasia. ACTA2(-/-) mice showed increased neointimal formation following vascular injury in vivo, and SMCs explanted from these mice demonstrated increased proliferation and migration. Loss of α-SMA induced hyperplasia through focal adhesion (FA) rearrangement, FA kinase activation, re-localization of p53 from the nucleus to the cytoplasm and increased expression and ligand-independent activation of platelet-derived growth factor receptor beta (Pdgfr-β). Disruption of α-SMA in wild-type SMCs also induced similar cellular changes. Imatinib mesylate inhibited Pdgfr-β activation and ACTA2(-/-) SMC proliferation in vitro and neointimal formation with vascular injury in vivo. Loss of α-SMA leads to SMC hyperplasia in vivo and in vitro through a mechanism involving FAK, p53 and Pdgfr-β, supporting the hypothesis that SMC hyperplasia contributes to occlusive lesions in patients with ACTA2 missense mutations.

  • mutations in smooth muscle alpha actin ACTA2 cause coronary artery disease stroke and moyamoya disease along with thoracic aortic disease
    American Journal of Human Genetics, 2009
    Co-Authors: Christina L Papke, Ellen S. Regalado, Van Tranfadulu, Nili Avidan, Ralph J Johnson, Hariyadarshi Pannu, Marcia C Willing, Elizabeth Sparks, Reed E Pyeritz, Michael N Singh
    Abstract:

    The vascular smooth muscle cell (SMC)-specific isoform of α-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.

  • mutations in smooth muscle alpha actin ACTA2 lead to thoracic aortic aneurysms and dissections
    Nature Genetics, 2007
    Co-Authors: Hariyadarshi Pannu, Christina L Papke, Van Tranfadulu, Nili Avidan, Elizabeth Sparks, Robert K Yu, Scott Bourgeois, Anthony L Estrera, Hazim J Safi, David J Amor
    Abstract:

    Mutations in smooth muscle α-actin ( ACTA2 ) lead to thoracic aortic aneurysms and dissections

Sarah J. Childs - One of the best experts on this subject based on the ideXlab platform.

  • Loss of miR26a morphants leads to increased expression of vSMC genes and ACTA2-positive vSMCs.
    2019
    Co-Authors: Charlene Watterston, Lei Zeng, Abidemi Onabadejo, Sarah J. Childs
    Abstract:

    A-B) Representative ventral views of 4 dpf Tg(BRE:EGFP); Tg(ACTA2:mCherry) embryos. Scr. Control embryos (A-A”) and miR26a morphant embryos (B-B”) showing qualitative upregulation of BRE:EGFP in the ventral aorta (VA) and pharyngeal arch arteries (PAA). C) Quantification of green fluorescent marker (BRE:EGFP) along the VA, taken from the highlighted yellow region in A’ and B’, and represented as corrected total cell fluorescence (CTCF) (N = 3, miR26a MO n = 15, Scr. Control n = 12, Unpaired t test, ****p< 0.0001 as compared to control, error bars = SEM). D) Quantification of ACTA2 positive cell number on VA and PAAs, within area outlined in A” and B”. Number of ACTA2 positive cells is significantly increased in miR26a morphants (N = 3, miR26a MO n = 18, Scr. Control n = 15, Unpaired t test, ****p< 0.0001 as compared to control, error bars = SEM). E and F) Measurement of vSMC height (yellow axis) from the endothelium (white dashed line). Representative images of ventral aorta (from insets), Scr. Control (E) and miR26a morphants (F). G) Quantification of average vessel heights along the length of the VA (N = 3, miR26a MO n = 18, Scr. Control n = 13, Student's two-tailed t-test, ****p< 0.0001 as compared to control, error bars = SEM). H) RT-qPCR quantification of vSMC differentiation genes in injected controls and miR26a morphants (n = 3). RT-qPCR data show the mean ± SEM, Student's two-tailed t-test *p 

  • an α smooth muscle actin ACTA2 αsma zebrafish transgenic line marking vascular mural cells and visceral smooth muscle cells
    PLOS ONE, 2014
    Co-Authors: Thomas Whitesell, Massimo Santoro, Regan M Kennedy, Alyson D Carter, Evvilynn Rollins, Sonja Georgijevic, Sarah J. Childs
    Abstract:

    Mural cells of the vascular system include vascular smooth muscle cells (SMCs) and pericytes whose role is to stabilize and/or provide contractility to blood vessels. One of the earliest markers of mural cell development in vertebrates is α smooth muscle actin (ACTA2; αsma), which is expressed by pericytes and SMCs. In vivo models of vascular mural cell development in zebrafish are currently lacking, therefore we developed two transgenic zebrafish lines driving expression of GFP or mCherry in ACTA2-expressing cells. These transgenic fish were used to trace the live development of mural cells in embryonic and larval transgenic zebrafish. ACTA2:EGFP transgenic animals show expression that largely mirrors native ACTA2 expression, with early pan-muscle expression starting at 24 hpf in the heart muscle, followed by skeletal and visceral muscle. At 3.5 dpf, expression in the bulbus arteriosus and ventral aorta marks the first expression in vascular smooth muscle. Over the next 10 days of development, the number of ACTA2:EGFP positive cells and the number of types of blood vessels associated with mural cells increases. Interestingly, the mural cells are not motile and remain in the same position once they express the ACTA2:EGFP transgene. Taken together, our data suggests that zebrafish mural cells develop relatively late, and have little mobility once they associate with vessels.

  • An α-smooth muscle actin (ACTA2/αsma) zebrafish transgenic line marking vascular mural cells and visceral smooth muscle cells.
    PloS one, 2014
    Co-Authors: Thomas Whitesell, Massimo Santoro, Regan M Kennedy, Alyson D Carter, Evvilynn Rollins, Sonja Georgijevic, Sarah J. Childs
    Abstract:

    Mural cells of the vascular system include vascular smooth muscle cells (SMCs) and pericytes whose role is to stabilize and/or provide contractility to blood vessels. One of the earliest markers of mural cell development in vertebrates is α smooth muscle actin (ACTA2; αsma), which is expressed by pericytes and SMCs. In vivo models of vascular mural cell development in zebrafish are currently lacking, therefore we developed two transgenic zebrafish lines driving expression of GFP or mCherry in ACTA2-expressing cells. These transgenic fish were used to trace the live development of mural cells in embryonic and larval transgenic zebrafish. ACTA2:EGFP transgenic animals show expression that largely mirrors native ACTA2 expression, with early pan-muscle expression starting at 24 hpf in the heart muscle, followed by skeletal and visceral muscle. At 3.5 dpf, expression in the bulbus arteriosus and ventral aorta marks the first expression in vascular smooth muscle. Over the next 10 days of development, the number of ACTA2:EGFP positive cells and the number of types of blood vessels associated with mural cells increases. Interestingly, the mural cells are not motile and remain in the same position once they express the ACTA2:EGFP transgene. Taken together, our data suggests that zebrafish mural cells develop relatively late, and have little mobility once they associate with vessels.

  • Smooth muscle markers are restricted to the developing cardiac outflow tract by 56 hpf.
    2014
    Co-Authors: Thomas R. Whitesell, Regan M Kennedy, Alyson D Carter, Evvilynn Rollins, Sonja Georgijevic, Massimo M. Santoro, Sarah J. Childs
    Abstract:

    (A) At 56 hpf, ACTA2 expression is restricted to the developing BA. (B,C) Double transgenic Tg(ACTA2:EGFP)ca7; Tg(kdrl:mCherry)ci5 embryo shows expression of EGFP in both the atrium and ventricle of the heart at 56 hpf, but not in the BA. (D) ACTA2 expression is evident at 78 hpf in the BA in both wholemount and cross section (E) and in transgenic animals (F). (G–I) Expression of ACTA2 continues to be restricted to the BA and ventral aorta (VA) at 100 hpf by in situ hybridization and in transgenic fish. (J–O): Cross sections of the 22 dpf BA show a multilamellar arterial phenotype as visualized by hematoxylin and eosin staining (J), in situ hybridization of ACTA2 (K) and transgenic GFP (nuclei stained blue with DAPI, L). The bulbus vascular wall consists of three layers: an inner intima, middle media, and outer adventitia (Ad, separated by black lines in J). The intima is endothelial (arrowheads point to nuclei of endothelial cells). The media consists of 3–4 cell-thick layers of vascular smooth muscle cells (M, arrows point to nuclei of SMCs). In comparison to the BA, the vascular wall of the VA at 22 dpf is thin (M) but expresses ACTA2 by in situ hybridization (N) and GFP in transgenic animals (O). The endothelium of VA is covered by a thin layer of SMCs (arrowheads point to nuclei of SMCs). (P) In situ hybridization of the wholemount adult heart shows strong staining in the bulbus arteriosus, but not ventricle or atrium, which is localized to the myocardial wall in cross section (Q). (R) Wholemount dissected ACTA2:EGFP transgenic heart shows stronger expression of GFP in the bulbus arteriosus as compared to ventricle. Staining is also continuous with the ventral aorta. In B,C, F, I, and R, green expression is ACTA2:EGFP transgene. Scale bar in B, C, F, and I is 100 µm. Scale bar in E, H, and Q is 50 µm. Scale bar in K, L, N, and O is 20 µm.

  • ACTA2 promoter/enhancer construct design and expression in zebrafish.
    2014
    Co-Authors: Thomas R. Whitesell, Regan M Kennedy, Alyson D Carter, Evvilynn Rollins, Sonja Georgijevic, Massimo M. Santoro, Sarah J. Childs
    Abstract:

    (A) A zebrafish (Dr) enhancer/promoter construct was constructed from the proximal promoter and first intron sequence of the zebrafish ACTA2 gene, and contains three highly conserved CArG binding sites also found in the mouse (Mm) ACTA2 proximal promoter and first intron. (B) Comparison of zebrafish CaRG boxes A and B in zebrafish, tilapia and medaka. (C,D) By wholemount in situ hybridization, ACTA2 shows strong expression in the gut (g) at 72 hpf (B), and expressed in the gut, swim bladder (sb), ventral aorta (va), floor plate (fp), aortic arch arteries (aaa), and bulbus arteriosus (ba) at 100 hpf (C). (E,F) Co-localization of wholemount in situ hybridization ACTA2 and anti-GFP staining of the ACTA2:GFP transgene shows strong expression in the aortic arch arteries (aaa) at 100 hpf. (G,H,I) 4 dpf ACTA2:EGFP transgenic fish (H) stained with Tagln rabbit polyclonal antibody (G). Merge (I) shows co-localization between ACTA2:GFP and Tagln. Arrowheads in G–I depict vascular mural cells. Scale bar in G represents 20 µm.

Thomas Whitesell - One of the best experts on this subject based on the ideXlab platform.

  • foxc1 is required for embryonic head vascular smooth muscle differentiation in zebrafish
    Developmental Biology, 2019
    Co-Authors: Thomas Whitesell, Paul W Chrystal, Jaeryeon Ryu, Nicole Munsie, Ann S Grosse, Curtis R French, Matthew L Workentine, Lihua Julie Zhu, Andrew J Waskiewicz, Ordan J Lehmann
    Abstract:

    Vascular smooth muscle of the head derives from neural crest, but developmental mechanisms and early transcriptional drivers of the vSMC lineage are not well characterized. We find that in early development, the transcription factor foxc1b is expressed in mesenchymal cells that associate with the vascular endothelium. Using timelapse imaging, we observe that foxc1b expressing mesenchymal cells differentiate into ACTA2 expressing vascular mural cells. We show that in zebrafish, while foxc1b is co-expressed in ACTA2 positive smooth muscle cells that associate with large diameter vessels, it is not co-expressed in capillaries where pdgfrβ positive pericytes are located. In addition to being an early marker of the lineage, foxc1 is essential for vSMC differentiation; we find that foxc1 loss of function mutants have defective vSMC differentiation and that early genetic ablation of foxc1b or ACTA2 expressing populations blocks vSMC differentiation. Furthermore, foxc1 is expressed upstream of ACTA2 and is required for ACTA2 expression in vSMCs. Using RNA-Seq we determine an enriched intersectional gene expression profile using dual expression of foxc1b and ACTA2 to identify novel vSMC markers. Taken together, our data suggests that foxc1 is a marker of vSMCs and plays a critical functional role in promoting their differentiation.

  • an α smooth muscle actin ACTA2 αsma zebrafish transgenic line marking vascular mural cells and visceral smooth muscle cells
    PLOS ONE, 2014
    Co-Authors: Thomas Whitesell, Massimo Santoro, Regan M Kennedy, Alyson D Carter, Evvilynn Rollins, Sonja Georgijevic, Sarah J. Childs
    Abstract:

    Mural cells of the vascular system include vascular smooth muscle cells (SMCs) and pericytes whose role is to stabilize and/or provide contractility to blood vessels. One of the earliest markers of mural cell development in vertebrates is α smooth muscle actin (ACTA2; αsma), which is expressed by pericytes and SMCs. In vivo models of vascular mural cell development in zebrafish are currently lacking, therefore we developed two transgenic zebrafish lines driving expression of GFP or mCherry in ACTA2-expressing cells. These transgenic fish were used to trace the live development of mural cells in embryonic and larval transgenic zebrafish. ACTA2:EGFP transgenic animals show expression that largely mirrors native ACTA2 expression, with early pan-muscle expression starting at 24 hpf in the heart muscle, followed by skeletal and visceral muscle. At 3.5 dpf, expression in the bulbus arteriosus and ventral aorta marks the first expression in vascular smooth muscle. Over the next 10 days of development, the number of ACTA2:EGFP positive cells and the number of types of blood vessels associated with mural cells increases. Interestingly, the mural cells are not motile and remain in the same position once they express the ACTA2:EGFP transgene. Taken together, our data suggests that zebrafish mural cells develop relatively late, and have little mobility once they associate with vessels.

  • An α-smooth muscle actin (ACTA2/αsma) zebrafish transgenic line marking vascular mural cells and visceral smooth muscle cells.
    PloS one, 2014
    Co-Authors: Thomas Whitesell, Massimo Santoro, Regan M Kennedy, Alyson D Carter, Evvilynn Rollins, Sonja Georgijevic, Sarah J. Childs
    Abstract:

    Mural cells of the vascular system include vascular smooth muscle cells (SMCs) and pericytes whose role is to stabilize and/or provide contractility to blood vessels. One of the earliest markers of mural cell development in vertebrates is α smooth muscle actin (ACTA2; αsma), which is expressed by pericytes and SMCs. In vivo models of vascular mural cell development in zebrafish are currently lacking, therefore we developed two transgenic zebrafish lines driving expression of GFP or mCherry in ACTA2-expressing cells. These transgenic fish were used to trace the live development of mural cells in embryonic and larval transgenic zebrafish. ACTA2:EGFP transgenic animals show expression that largely mirrors native ACTA2 expression, with early pan-muscle expression starting at 24 hpf in the heart muscle, followed by skeletal and visceral muscle. At 3.5 dpf, expression in the bulbus arteriosus and ventral aorta marks the first expression in vascular smooth muscle. Over the next 10 days of development, the number of ACTA2:EGFP positive cells and the number of types of blood vessels associated with mural cells increases. Interestingly, the mural cells are not motile and remain in the same position once they express the ACTA2:EGFP transgene. Taken together, our data suggests that zebrafish mural cells develop relatively late, and have little mobility once they associate with vessels.

David J Amor - One of the best experts on this subject based on the ideXlab platform.

Hariyadarshi Pannu - One of the best experts on this subject based on the ideXlab platform.

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