Lack of PI 3-kinase isoform p110alpha in smooth muscle cells impairs aortic wall homoeostasis and thus promotes aortic aneurysm formation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Vantler ◽  
E Berghausen ◽  
M Zierden ◽  
M Mollenhauer ◽  
D Mehrkens ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Aortic Wall ◽  
Muscle Cells ◽  
Vascular Wall ◽  
Aortic Diameter ◽  
Funding Source ◽  
Wild Type ◽  
Tunica Media

Abstract Background In smooth muscle cells (SMCs), the PI 3-kinase isoform p110α mediates receptor tyrosine kinase dependent proliferation, chemotaxis and cell survival. Since mice, harbouring a smooth muscle specific p110α deficiency (SM-p110α−/−), display reduced vascular wall thickness, we hypothesized that SM-p110α−/− mice might be prone to aortic aneurysm (AA) formation. The pathogenesis of AA is characterized by increased dedifferentiation of SMCs, extracellular matrix (ECM) degeneration and inflammation in the aortic wall. Herein, we investigated how p110α-dependent signal transduction in SMCs affects these processes. Methods and results We examined AA formation in SM-p110α−/− mice and wild-type littermates using the “porcine pancreatic elastase” (PPE) AA model. PPE was infused into the infrarenal aorta to induce AA formation. Ultrasound examination of the aorta revealed an enlarged aortic diameter in all PPE-treated mice. The aortic diameter in SM-p110α−/− mice (0.46±0.12 mm) was significantly increased compared to wild-type animals (0.18±0.03 mm, p<0.01). These data indicate a protective function of p110α in AA formation. Immunocytochemical examination of the tunica media of PPE-perfused SM-p110α−/− mice revealed significantly increased infiltration of CD45+ leukocytes. In particular, the number of MOMA-2+ monocytes / macrophages in the vessel wall was significantly increased indicating elevated inflammation of the aortic wall during AA progression in comparison to wild-type control mice. Ultrastructural analysis of aortic wall morphology in SM-p110α−/− mice using transmission electron microscopy (TEM) showed a deranged tunica media and increased apoptotic cell death. In addition, the media thickness in the abdominal aorta was significantly reduced in SM-p110α−/− mice (29.0±3.1 μm vs. 42.5±4.1 μm). Western blots demonstrated a reduced elastin and fibrillin expression in SMCs from SM-p110α−/− mice. p110α−/− SMCs showed significantly reduced expression of differentiation markers SM-α-actin and SM-MHC. In addition, aortic p110α-deficient SMCs were significantly impaired in their ability to proliferate and migrate. These findings indicate that p110α−/− SMCs are neither differentiated nor dedifferentiated and have therefore largely lost their plasticity. Consequently, p110α deficiency significantly diminished responsiveness of aortic rings to vasodilator acetylcholine and NO-donor nitroglycerin, further indicating impaired contractility of SMCs. Mechanistically, we demonstrated that PDGF and insulin induced phosphorylation and inactivation of key regulators of SMC differentiation and dedifferentiation, Foxo4 and GSK3b, respectively, were abrogated in p110α−/− SMCs. Conclusion These data show that deficiency of p110α in SMCs promotes the formation and progression of AA. Causative are impaired SMC plasticity and ECM homeostasis as well as inflammatory processes in the vascular wall. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

Smooth muscle cell-specific SOCS3 deficiency promote pericardial fibrosis and diastolic dysfunction in aging mice

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Yanai ◽  
H Yasukawa ◽  
K Mawatari ◽  
T Sasaki ◽  
J Takahashi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Diastolic Dysfunction ◽  
Interstitial Fibrosis ◽  
Muscle Cells ◽  
Left Ventricular ◽  
Funding Source ◽  
Wild Type

Abstract Background Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible negative regulator of signal transducer and activator of transcription-3 (STAT3) signaling pathway. We have previously shown that cardiac-specific SOCS3 deficiency spontaneously develop cardiac dysfunction with advanced age. However, the role of SOCS3 in smooth muscle cells in cardiovascular pathophysiology remains elusive. In this study, we determined whether STAT3 and SOCS3 in smooth muscle cells would play a role in cardiovascular pathophysiology. Methods and results To target inactivation of the SOCS3 gene to smooth muscle cells, SOCS3-flox mice were bred with transgenic mice expressing Cre recombinase under control of the mouse SM22-α promoter (sm-SOCS3-KO mice). Left ventricular weight to body weight ratio was significantly increased in sm-SOCS3-KO mice compared with wild-type mice at 12 months of age (p<0.05). Echocardiographic analyses of smSOCS3-KO mice showed significantly increased left ventricular diastolic dysfunction compared with wild-type from 12 months of age (p<0.05). Sirius-red staining revealed that thickness of pericardium and cardiac interstitial fibrosis in sm-SOCS3-KO mice were markedly greater compared with wild-type mice at 12 months of age (p<0.05). Western blot analyses showed that phosphorylated STAT3 was significantly increased in sm-SOCS3-KO hearts compared with wild-type mice at 12 months of age (p<0.05), whereas no significant differences were observed at 2 months of age. To investigate the mechanism that gave rise to promoted cardiac fibrosis and diastolic dysfunction during aging in sm-SOCS3-KO, we conducted a real-time PCR array analysis for fibrosis. The expression of pro-fibrotic CTGF (connective tissue growth factor), PDGFb (platelet growth factor-b), and TGF (transforming growth factor) family genes including TGFb1, TGFb2, and TGFb3, were significantly higher in sm-SOCS3-KO hearts than those in wild-type at 6 months of age. Conclusion Thus, smooth muscle cell-specific SOCS3 deletion induces increased pericardial fibrosis, cardiac interstitial fibrosis, and increased diastolic dysfunction in aging mice, possibly through the augmentation of pro-fibrotic growth factors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant JSPS KAKENHI

scholarly journals Strong Signs for a Weak Wall in Tricuspid Aortic Valve Associated Aneurysms and a Role for Osteopontin in Bicuspid Aortic Valve Associated Aneurysms

2019 ◽  
Vol 20 (19) ◽  
pp. 4782 ◽  
Author(s):  
Christian Stern ◽  
Bernhard Scharinger ◽  
Adrian Tuerkcan ◽  
Clemens Nebert ◽  
Teresa Mimler ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Bicuspid Aortic Valve ◽  
Aortic Wall ◽  
Muscle Cells ◽  
Vascular Wall ◽  
Aortic Tissue

Central processes in the pathogenesis of TAV- (tricuspid aortic valve) and BAV- (bicuspid aortic valve) associated ascending thoracic aortic aneurysm (ATAA) development are still unknown. To gain new insights, we have collected aortic tissue and isolated smooth muscle cells of aneurysmal tissue and subjected them to in situ and in vitro analyses. We analyzed aortic tissue from 78 patients (31 controls, 28 TAV-ATAAs, and 19 BAV-ATAAs) and established 30 primary smooth muscle cell cultures. Analyses included histochemistry, immuno-, auto-fluorescence-based image analyses, and cellular analyses including smooth muscle cell contraction studies. With regard to TAV associated aneurysms, we observed a strong impairment of the vascular wall, which appears on different levels—structure and dimension of the layers (reduced media thickness, increased intima thickness, atherosclerotic changes, degeneration of aortic media, decrease of collagen, and increase of elastic fiber free area) as well as on the cellular level (accumulation of fibroblasts/myofibroblasts, and increase in the number of smooth muscle cells with a reduced alpha smooth muscle actin (α-SM actin) content per cell). The pathological changes in the aortic wall of BAV patients were much less pronounced—apart from an increased expression of osteopontin (OPN) in the vascular wall which stem from smooth muscle cells, we observed a trend towards increased calcification of the aortic wall (increase significantly associated with age). These observations provide strong evidence for different pathological processes and different disease mechanisms to occur in BAV- and TAV-associated aneurysms.

Endothelium in Aortic Aneurysm Disease: New Insights

2020 ◽  
Vol 27 (7) ◽  
pp. 1081-1088 ◽  
Author(s):  
Eleftherios Spartalis ◽  
Michael Spartalis ◽  
Antonios Athanasiou ◽  
Stavroula A. Paschou ◽  
Nikolaos Patelis ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Flow ◽  
Smooth Muscle ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Aortic Wall ◽  
Muscle Cells ◽  
Aortic Aneurysms

Inflammation is recognized as a fundamental element in the development and growth of aortic aneurysms. Aortic aneurysm is correlated with aortic wall deformities and injury, as a result of inflammation, matrix metalloproteinases activation, oxidative stress, and apoptosis of vascular smooth muscle cells. The endothelial wall has a critical part in the inflammation of the aorta and endothelial heterogeneity has proven to be significant for modeling aneurysm formation. Endothelial shear stress and blood flow affect the aortic wall through hindrance of cytokines and adhesion molecules excreted by endothelial cells, causing reduction of the inflammation process in the media and adventitia. This pathophysiological process results in the disruption of elastic fibers, degradation of collagen fibers, and destruction of vascular smooth muscle cells. Consequently, the aortic wall is impaired due to reduced thickness, decreased mechanical function, and cannot tolerate the impact of blood flow leading to aortic expansion. Surgery is still considered the mainstay therapy for large aortic aneurysms. The prevention of aortic dilation, though, is based on the hinderance of endothelial dysregulation with drugs, the reduction of reactive oxygen and nitrogen species, and also the reduction of pro-inflammatory molecules and metalloproteinases. Further investigations are required to enlighten the emerging role of endothelial cells in aortic disease.

scholarly journals Role of Perivascular Adipose Tissue-Derived Adiponectin in Vascular Homeostasis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1485
Author(s):  
Adrian Sowka ◽  
Pawel Dobrzyn
Keyword(s):  
Endothelial Cells ◽  
Adipose Tissue ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Vascular Wall ◽  
Whole Body ◽  
Perivascular Adipose Tissue

Studies of adipose tissue biology have demonstrated that adipose tissue should be considered as both passive, energy-storing tissue and an endocrine organ because of the secretion of adipose-specific factors, called adipokines. Adiponectin is a well-described homeostatic adipokine with metabolic properties. It regulates whole-body energy status through the induction of fatty acid oxidation and glucose uptake. Adiponectin also has anti-inflammatory and antidiabetic properties, making it an interesting subject of biomedical studies. Perivascular adipose tissue (PVAT) is a fat depot that is conterminous to the vascular wall and acts on it in a paracrine manner through adipokine secretion. PVAT-derived adiponectin can act on the vascular wall through endothelial cells and vascular smooth muscle cells. The present review describes adiponectin’s structure, receptors, and main signaling pathways. We further discuss recent studies of the extent and nature of crosstalk between PVAT-derived adiponectin and endothelial cells, vascular smooth muscle cells, and atherosclerotic plaques. Furthermore, we argue whether adiponectin and its receptors may be considered putative therapeutic targets.

Loss of smooth muscle SDF-1/CXCL12 leads to cardiac hypertrophy and aortic valve stenosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.K Ghadge ◽  
M Messner ◽  
H Seiringer ◽  
T Zeller ◽  
D Boernigen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Stenosis ◽  
Cardiac Hypertrophy ◽  
Smooth Muscle Cells ◽  
Aortic Valve Stenosis ◽  
Cardiac Fibrosis ◽  
Muscle Cells ◽  
Funding Source ◽  
Lineage Tracking

Abstract Background Stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptors CXCR4/CXCR7 have prominent role in cardiovascular development and myocardial repair following ischemic injury. Nevertheless, detailed mechanisms of the cell specific role of SDF-1 are poorly understood. Since SDF-1-EGFP lineage tracking revealed high expression of SDF-1 in smooth muscle cells, we aimed to investigate the cell specific role by generating a smooth muscle cell specific SDF-1 (SM-SDF-1−/−) knockout mouse model. Methods SDF-1 expression was analyzed utilizing SDF-1-EGFP reporter mice. Conditional SM-SDF-1 KO mice were generated using Tagln-Cre; SDF-1fl/fl mice. Hearts were analysed with histology and high-resolution episcopic microscopy. Cardiac function was assessed utilizing echocardiography. RNAseq, qRT-PCR, flow cytometry and western blotting were performed. Cardiac fibrosis, apoptotic index, cell proliferation, aortic valve calcification were analyzed. SM-SDF-1−/− mice were treated with the CXCR7 agonist TC14012 (10mg/kg/I.P). Results SDF-1-EGFP lineage tracking and immunofluorescence revealed high expression of SDF-1 particularly in smooth muscle cells and less frequently in perivascular and endothelial cells. Conditional SM-SDF-1−/− mice showed a high pre- and perinatal mortality (50%). Immunohistochemistry of SM-SDF-1−/− mice revealed severe cardiac hypertrophy, associated with increased cardiac fibrosis, apoptotic cell death, thinned and dilated arteries and significantly decreased M2 like CD11b+/CD206+ cells. Echocardiography confirmed concentric hypertrophy, with decreased stroke volume. As a possible reason for cardiac hypertrophy, SDF-1 mutants exhibited aortic stenosis due to aortic valve thickening associated with downregulation of the SDF-1 co-receptor CXCR7. We further noticed increased plasma levels of SDF-1 in aortic stenosis patients suggesting a cardioprotective role. Transcriptome analyses from KO hearts showed an abnormal extracellular matrix (ECM) remodelling with a specific upregulation of the important valve related proteoglycans Versican, Glycan. Western blot analysis revealed activation of AKT and ERK, whereas CXCR7 expression was significantly downregulated in KO mice. To rescue the phenotype we treated KO mice with the CXCR7 agonist (TC14012) which partially attenuated aortic valve remodelling through activation of the ERK signalling pathway. Conclusion Our data suggest that SDF-1 is critically involved in maintaining the homeostasis of the aortic valve by regulating CXCR7 signalling. Pharmacological activation of CXCR7 might be a promising therapeutic target to limit the progression of aortic valve stenosis. Ghadge_SM-SDF-1−/− Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund, Austrian research promotion agency

Femoral artery neointimal hyperplasia is reduced after wire injury in Ref-1+/− mice

2007 ◽  
Vol 292 (1) ◽  
pp. H516-H521 ◽  
Author(s):  
David L. Basi ◽  
Neeta Adhikari ◽  
Ami Mariash ◽  
Qinglu Li ◽  
Esther Kao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Femoral Artery ◽  
Cellular Response ◽  
Fas Ligand ◽  
Neointimal Hyperplasia ◽  
Muscle Cells ◽  
Wild Type

Redox factor-1 (Ref-1) is a multifunctional protein that regulates redox, DNA repair, and the response to cell stress. We previously demonstrated that Ref-1+/− mice exhibit a significantly reduced Ref-1 mRNA and protein levels within the vasculature, which are associated with increased oxidative stress. The goal of this study was to test the hypothesis that partial loss of Ref-1 altered the cellular response to vascular injury. Fourteen days after femoral artery wire injury, we found that vessel intima-to-media ratio was significantly reduced in Ref-1+/− mice compared with that in wild-type mice ( P < 0.01). Bromodeoxyuridine labeling and transferase-mediated dUTP nick-end labeling staining at 14 days did not differ in the Ref-1+/− mice. In vitro studies found no significant changes in either serum-induced proliferation or baseline apoptosis in Ref-1+/− vascular smooth muscle cells. Exposure to Fas ligand; however, did result in increased susceptibility of Ref-1+/− vascular smooth muscle cells to apoptosis ( P < 0.001). Ref-1+/− mice exhibited an increase in circulating baseline levels of IL-10, IL-1α, and VEGF compared with those in wild-type mice but a marked impairment in these pathways in response to injury. In sum, loss of a single allele of Ref-1 is sufficient to reduce intimal lesion formation and to alter circulating cytokine and growth factor expression.

scholarly journals Histochemical and immunohistochemical analysis of ruptured atherosclerotic abdominal aortic aneurysm wall

2010 ◽  
Vol 67 (12) ◽  
pp. 959-964 ◽  
Author(s):  
Irena Tanaskovic ◽  
Aleksandra Mladenovic-Mihailovic ◽  
Slavica Usaj-Knezevic ◽  
Vesna Stankovic ◽  
Aleksandar Aleksic ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Periodic Acid ◽  
Muscle Cells ◽  
Foam Cells ◽  
Abdominal Aortic ◽  
S 100 ◽  
The Media

Background/Aim. The main complication of the atherosclerotic abdominal aortic aneurism (AAA) is her rupture that begins with lesion in intima and rupture. The purpose of this work was to determine immunocytochemical and morphofunctional characteristics of the cells in aortic wall in ruptured atherosclerotic abdominal aortic aneurysm. Method. During the course of this study, 20 samples of atherosclerotic AAA were analyzed, all of them obtained during authopsy. The samples were fixed in 4% formalin and embedded in paraffin. Sections of 5 ?m thickness were stained histochemically (of Heidenhain azan stain and Periodic acid Schiff - PAS stain) and immunocytochemically using a DAKO LSAB+/HRP technique to identify ?-smooth muscle actin (?-SMA), vimentin, myosin heavy chains (MHC), desmin, S-100 protein, CD45 and CD68 (DAKO specification). Results. The results of our study showed that ruptured atherosclerotic AAA is characterized by a complete absence of endothelial cells, the disruption of basal membrane and internal elastic lamina, as well as a presence of the remains of hypocellular complicated atherosclerotic lesion in intima. On the plaque margins, as well as in the media, smooth muscle cells (SMCs) are present, which express a ?-SMA and vimentin (but without MHC or desmin expression), as well as leukocyte infiltration, and a large number of foam cells. Some of the foam cells show a CD68-immunoreactivity, while the others show vimentin- and S-100 protein-immunoreactivity. Media is thinned out with a disorganized elastic lamellas, while adventitia is characterized by inflammatory inflitrate (infection). Conclusion. Rupture of aneurysm occurs from the primary intimal disruption, which spreads into thinned out media and adventitia. Rupture is caused by unstable atherom, hypocellularity, loss of contractile characteristics of smooth muscle cells in intima and media, neovascularization of the media, as well as by the activity of the macrophages in the lesion.

scholarly journals Transcriptome alterations of vascular smooth muscle cells in aortic wall of myocardial infarction patients

Data in Brief ◽  
2018 ◽  
Vol 17 ◽  
pp. 1112-1135 ◽  
Author(s):  
Thidathip Wongsurawat ◽  
Chin Cheng Woo ◽  
Antonis Giannakakis ◽  
Xiao Yun Lin ◽  
Esther Sok Hwee Cheow ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Aortic Wall ◽  
Muscle Cells

Peri-Adventitial Delivery of Smooth Muscle Cells in Porous Collagen Scaffolds for Treatment of Experimental Abdominal Aortic Aneurysm

2021 ◽  
Author(s):  
Joscha Mulorz ◽  
Mahdis Shayan ◽  
Caroline Hu ◽  
Cynthia Alcazar ◽  
Alex H.P Chan ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vessel Wall ◽  
Muscle Cells ◽  
Collagen Scaffolds ◽  
Abdominal Aortic ◽  
Direct Delivery

Abdominal aortic aneurysm (AAA) is associated with the loss of vascular smooth muscle cells (SMCs) within the vessel wall. Direct delivery of therapeutic cells is challenging due to impaired mechanical...

Abstract 381: IL-19 Inhibits Atherosclerosis in LDLR-/- Mice by Modulating Cholesterol Uptake in Macrophages and Vascular Smooth Muscle Cells

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Khatuna Gabunia ◽  
Stephen P Ellison ◽  
James M Richards ◽  
Sheri E Kelemen ◽  
Michael V Autieri
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Atherosclerotic Plaque ◽  
Scavenger Receptor ◽  
Muscle Cells ◽  
Wild Type ◽  
Anti Inflammatory ◽  
M2 Phenotype

IL-19 is a recently described, putative anti-inflammatory cytokine which had previously been ascribed to be leukocyte specific. IL-19 is not detected in normal artery, but we detected IL-19 in multiple cell types in human atherosclerotic plaque suggesting a role for this interleukin in atherosclerosis. The purpose of this study was to determine whether administration of exogenous IL-19 could attenuate development of pre-formed atherosclerotic plaque, and to identify potential molecular mechanisms. LDLR-/- mice were fed high-fat diet for 12 weeks and then administered with 10ng/g/day IL-19 or PBS for an additional 8 weeks. En face analysis demonstrated that IL-19 could halt, but not reverse existing plaque (26.7+/-1.7%, 41.03+/-3.1%, 23.70+/-2.6% for baseline, PBS control, and IL-19-treated mice). Foam cell formation by macrophages and vascular smooth muscle cells (VSMC) is a hallmark event during atherosclerosis. Nothing has been reported regarding IL-19 effects on macrophage or VSMC lipid uptake; we therefore investigated whether IL-19 affects macrophage and VSMC cholesterol handling. Addition of IL-19 to wild-type bone marrow derived macrophages (BMDM) significantly promoted oxLDL uptake, conversely, BMDM from IL-19-/- mice had significantly less oxLDL uptake compared to wild-type BMDM. Addition of IL-19 to wild type BMDM significantly increased expression of scavenger receptor B1 (SR-B1), and decreased expression of inflammatory cytokines TNFα, IL-12b, MCP1. Interestingly, converse results were obtained with VSMC, as addition of IL-19 to wild-type VSMC decreased uptake of oxLDL ( p<0.05 ) and decreased expression of scavenger receptor CD36. VSMC isolated from IL-19-/- mice had increased uptake of oxLDL (p<0.0001). It is reported that M2 macrophages participate in plaque regression. IL-19 decreased IL-12b and significantly promoted the polarization of anti-inflammatory M2 phenotype in BMDM as evidenced by the increased expression of YM1 and IL-10 mRNA. These data demonstrate that IL-19 can inhibit progression of existing atherosclerotic plaque by modulating lipid metabolism in VSMC and macrophages and by promoting macrophage differentiation into an alternative, anti-inflammatory M2 phenotype.

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