Downregulation of the Yes-Associated Protein Is Associated with Extracellular Matrix Disorders in Ascending Aortic Aneurysms

Previous studies indicate that extracellular matrix (ECM) disorders lead to the apoptosis of Vascular Smooth Muscle Cells (VSMCs), which impairs the aortic wall by reducing the generation of elastic fibers, and ultimately result in ascending aortic aneurysm. The critical role of the Yes-associated protein (YAP) has been elucidated in cardiac/SMC proliferation during cardiovascular development. However, the association of YAP expression and extracellular matrix disorders in ascending aortic aneurysms is not clear. Here, we present for the first time that the downregulation of YAP in VSMCs is associated with ECM disorders of the media in ascending aortic aneurysms. We found that aortic ECM deteriorated with increased apoptotic VSMCs. Moreover, expression of YAP was dramatically reduced in the aortic walls of patients with ascending aortic aneurysms, while the normal aortic samples exhibited abundant YAP in the VSMCs. These results suggest that downregulation of YAP leads to apoptosis of VSMCs, which are essential for the homeostasis of the aortic wall. The resultant ECM disorders affect aortic structure and function and contribute to the development of ascending aortic aneurysms. In summary, through assessment of clinical samples, we revealed the association between downregulation of YAP in VSMCs and the development of ascending aortic aneurysms, providing new insight into the pathogenesis of this disease.

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Quantitative not qualitative histology differentiates aneurysmal from nondilated ascending aortas and reveals a net gain of medial components

Scientific Reports ◽

10.1038/s41598-021-92659-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sameh Yousef ◽

Nana Matsumoto ◽

Issam Dabe ◽

Makoto Mori ◽

Alden B. Landry ◽

...

Keyword(s):

Extracellular Matrix ◽

Quantitative Assessment ◽

Cell Number ◽

Aortic Aneurysms ◽

Aortic Dilatation ◽

Adaptive Responses ◽

Cross Sectional ◽

Thoracic Aortic Aneurysms ◽

Medial Degeneration ◽

The Media

AbstractMedial degeneration is a common histopathological finding in aortopathy and is considered a mechanism for dilatation. We investigated if medial degeneration is specific for sporadic thoracic aortic aneurysms versus nondilated aortas. Specimens were graded by pathologists, blinded to the clinical diagnosis, according to consensus histopathological criteria. The extent of medial degeneration by qualitative (semi-quantitative) assessment was not specific for aneurysmal compared to nondilated aortas. In contrast, blinded quantitative assessment of elastin amount and medial cell number distinguished aortic aneurysms and referent specimens, albeit with marked overlap in results. Specifically, the medial fraction of elastin decreased from dilution rather than loss of protein as cross-sectional amount was maintained while the cross-sectional number, though not density, of smooth muscle cells increased in proportion to expansion of the media. Furthermore, elastic lamellae did not thin and interlamellar distance did not diminish as expected for lumen dilatation, implying a net gain of lamellar elastin and intralamellar cells or extracellular matrix during aneurysmal wall remodeling. These findings support the concepts that: (1) medial degeneration need not induce aortic aneurysms, (2) adaptive responses to altered mechanical stresses increase medial tissue, and (3) greater turnover, not loss, of mural cells and extracellular matrix associates with aortic dilatation.

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Extracellular Matrix Hydrogels Originated from Different Organs Mediate Tissue-Specific Properties and Function

International Journal of Molecular Sciences ◽

10.3390/ijms222111624 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11624

Author(s):

Tzila Davidov ◽

Yael Efraim ◽

Rotem Hayam ◽

Jacopo Oieni ◽

Limor Baruch ◽

...

Keyword(s):

Mechanical Properties ◽

Extracellular Matrix ◽

Pluripotent Stem Cells ◽

Physical And Mechanical Properties ◽

Tissue Specific ◽

Gene Expression Analyses ◽

Composition Structure ◽

Induced Pluripotent ◽

And Function ◽

First Time

Porcine extracellular matrix (pECM)-derived hydrogels were introduced, in recent years, aiming to benefit the pECM’s microstructure and bioactivity, while controlling the biomaterial’s physical and mechanical properties. The use of pECM from different tissues, however, offers tissue-specific features that can better serve different applications. In this study, pECM hydrogels derived from cardiac, artery, pancreas, and adipose tissues were compared in terms of composition, structure, and mechanical properties. While major similarities were demonstrated between all the pECM hydrogels, their distinctive attributes were also identified, and their substantial effects on cell-ECM interactions were revealed. Furthermore, through comprehensive protein and gene expression analyses, we show, for the first time, that each pECM hydrogel supports the spontaneous differentiation of induced pluripotent stem cells towards the resident cells of its origin tissue. These findings imply that the origin of ECM should be carefully considered when designing a biomedical platform, to achieve a maximal bioactive impact.

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Biomechanical and Microstructural Properties of Fibulin-5 Null Mice

ASME 2009 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2009-206435 ◽

2009 ◽

Author(s):

William Wan ◽

Hiromi Yanagisawa ◽

Rudolph L. Gleason

Keyword(s):

Extracellular Matrix ◽

Carotid Arteries ◽

Constitutive Relations ◽

Critical Role ◽

Model Development ◽

Mechanical Tests ◽

Elastic Fibers ◽

Microstructural Properties ◽

Vascular Mechanics ◽

Multiple Loading

Fibulin-5 is an extracellular matrix (ECM) protein that interacts with integrins and plays a critical role in organizing elastic fibers. Gross observation and histological examination reveal that carotid arteries from fibulin-5 knockout (fib5-/-) mice have disrupted elastic lamellae and are more tortuous [1]. The properties of fibulin-5 null mice provide a unique platform for developing constituent based models for vascular mechanics. While numerous models for blood vessels exist, there is a need to relate measurable microstructural metrics of structurally-based constitutive relations. We performed mechanical tests on carotid arteries from wildtype (WT) and fib5-/-mice and imaged live vessels under multiple loading scenarios to quantify microstructure during deformation. We also fit experimental results to a constitutive relation based on Holzapfel’s model [2]. These results provide a basis for further model development.

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Apelin expression deficiency in mice contributes to vascular stiffening by extracellular matrix remodeling of the aortic wall

Scientific Reports ◽

10.1038/s41598-021-01735-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Beatrice Romier ◽

Cédric Dray ◽

Laetitia Vanalderwiert ◽

Amandine Wahart ◽

Thinhinane Hocine ◽

...

Keyword(s):

Extracellular Matrix ◽

Adipose Tissue ◽

Pulse Wave Velocity ◽

Aortic Wall ◽

Pulse Wave ◽

Elastic Fibers ◽

Cathepsin S ◽

Wild Type ◽

Collagen Accumulation ◽

Vascular Stiffening

AbstractNumerous recent studies have shown that in the continuum of cardiovascular diseases, the measurement of arterial stiffness has powerful predictive value in cardiovascular risk and mortality and that this value is independent of other conventional risk factors, such as age, cholesterol levels, diabetes, smoking, or average blood pressure. Vascular stiffening is often the main cause of arterial hypertension (AHT), which is common in the presence of obesity. However, the mechanisms leading to vascular stiffening, as well as preventive factors, remain unclear. The aim of the present study was to investigate the consequences of apelin deficiency on the vascular stiffening and wall remodeling of aorta in mice. This factor freed by visceral adipose tissue, is known for its homeostasic role in lipid and vascular metabolisms, or again in inflammation. We compared the level of metabolic markers, inflammation of white adipose tissue (WAT), and aortic wall remodeling from functional and structural approaches in apelin-deficient and wild-type (WT) mice. Apelin-deficient mice were generated by knockout of the apelin gene (APL-KO). From 8 mice by groups, aortic stiffness was analyzed by pulse wave velocity measurements and by characterizations of collagen and elastic fibers. Mann–Whitney statistical test determined the significant data (p < 5%) between groups. The APL-KO mice developed inflammation, which was associated with significant remodeling of visceral WAT, such as neutrophil elastase and cathepsin S expressions. In vitro, cathepsin S activity was detected in conditioned medium prepared from adipose tissue of the APL-KO mice, and cathepsin S activity induced high fragmentations of elastic fiber of wild-type aorta, suggesting that the WAT secretome could play a major role in vascular stiffening. In vivo, remodeling of the extracellular matrix (ECM), such as collagen accumulation and elastolysis, was observed in the aortic walls of the APL-KO mice, with the latter associated with high cathepsin S activity. In addition, pulse wave velocity (PWV) and AHT were increased in the APL-KO mice. The latter could explain aortic wall remodeling in the APL-KO mice. The absence of apelin expression, particularly in WAT, modified the adipocyte secretome and facilitated remodeling of the ECM of the aortic wall. Thus, elastolysis of elastic fibers and collagen accumulation contributed to vascular stiffening and AHT. Therefore, apelin expression could be a major element to preserve vascular homeostasis.

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Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

10.1101/2020.01.30.925412 ◽

2020 ◽

Cited By ~ 1

Author(s):

Giulia L.M. Boezio ◽

Anabela Bensimon-Brito ◽

Janett Piesker ◽

Stefan Guenther ◽

Christian S.M. Helker ◽

...

Keyword(s):

Extracellular Matrix ◽

Smooth Muscle ◽

Muscle Development ◽

Outflow Tract ◽

Aortic Aneurysms ◽

Type I ◽

Β Receptor ◽

And Function ◽

Cardiac Outflow

SummaryThe development of the cardiac outflow tract (OFT), which connects the heart to the great arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) cells. Defects in OFT development can lead to severe malformations, including aortic aneurysms, which have often been associated with impaired TGF-β signaling. To further investigate the role of TGF-β signaling in OFT formation, we generated zebrafish lacking the type I TGF-β receptor Alk5 and found a strikingly specific dilation of the OFT. alk5 mutants also exhibit increased EC numbers, extracellular matrix (ECM) and SMC disorganization. Surprisingly, endothelial-specific alk5 overexpression in alk5 mutants rescues both endothelial and SMC defects. Furthermore, modulation of the ECM gene fibulin-5, a TGF-β target, partially restores OFT morphology and function. These findings reveal a new requirement for endothelial TGF-β signaling in OFT morphogenesis and suggest an important role for the endothelium in the etiology of aortic malformations.

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Phenotypic and Functional Changes of Endothelial and Smooth Muscle Cells in Thoracic Aortic Aneurysms

International Journal of Vascular Medicine ◽

10.1155/2016/3107879 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 13

Author(s):

Anna Malashicheva ◽

Daria Kostina ◽

Aleksandra Kostina ◽

Olga Irtyuga ◽

Irina Voronkina ◽

...

Keyword(s):

Extracellular Matrix ◽

Smooth Muscle ◽

Aortic Valve ◽

Smooth Muscle Cells ◽

Aortic Wall ◽

Muscle Cells ◽

Aortic Aneurysms ◽

Cell Phenotype ◽

Functional Markers ◽

Thoracic Aortic Aneurysms

Thoracic aortic aneurysm develops as a result of complex series of events that alter the cellular structure and the composition of the extracellular matrix of the aortic wall. The purpose of the present work was to study the cellular functions of endothelial and smooth muscle cells from the patients with aneurysms of the thoracic aorta. We studied endothelial and smooth muscle cells from aneurysms in patients with bicuspid aortic valve and with tricuspid aortic valve. The expression of key markers of endothelial (CD31, vWF, and VE-cadherin) and smooth muscle (SMA, SM22α, calponin, and vimentin) cells as well extracellular matrix and MMP activity was studied as well as and apoptosis and cell proliferation. Expression of functional markers of endothelial and smooth muscle cells was reduced in patient cells. Cellular proliferation, migration, and synthesis of extracellular matrix proteins are attenuated in the cells of the patients. We show for the first time that aortic endothelial cell phenotype is changed in the thoracic aortic aneurysms compared to normal aortic wall. In conclusion both endothelial and smooth muscle cells from aneurysms of the ascending aorta have downregulated specific cellular markers and altered functional properties, such as growth rate, apoptosis induction, and extracellular matrix synthesis.

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Proximal aortic aneurysms: correlation of maximum aortic diameter and aortic wall thickness

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezab147 ◽

2021 ◽

Author(s):

Josephina Haunschild ◽

Sarah Jane Barnard ◽

Martin Misfeld ◽

Diyar Saeed ◽

Piroze Davierwala ◽

...

Keyword(s):

Aortic Valve ◽

Bicuspid Aortic Valve ◽

Wall Thickness ◽

Aortic Wall ◽

Positive Family History ◽

Aortic Aneurysms ◽

Aortic Diameter ◽

The Media ◽

Aortic Wall Thickness ◽

Relationship Of

Abstract OBJECTIVES The goal of therapy of proximal aortic aneurysms is to prevent an aortic catastrophe, e.g. acute dissection or rupture. The decision to intervene is currently based on maximum aortic diameter complemented by known risk factors like bicuspid aortic valve, positive family history or rapid growth rate. When applying Laplace’s law, wall tension is determined by pressure × radius divided by aortic wall thickness. Because current imaging modalities lack precision, wall thickness is currently neglected. The purpose of our study was therefore to correlate maximum aortic diameter with aortic wall thickness and known indices for adverse aortic events. METHODS Aortic samples from 292 patients were collected during cardiac surgery, of whom 158 presented with a bicuspid aortic valve and 134, with a tricuspid aortic valve. Aortic specimens were obtained during the operation and stored in 4% formaldehyde. Histological staining and analysis were performed to determine the thickness of the aortic wall. RESULTS Patients were 62 ± 13 years old at the time of the operation; 77% were men. The mean aortic dimensions were 44 mm, 41 mm and 51 mm at the aortic root, sinotubular junction and ascending aorta, respectively. Aortic valve stenosis was the most frequent (49%) valvular dysfunction, followed by aortic valve regurgitation (33%) and combined dysfunction (10%). The maximum aortic diameter at the ascending level did not correlate with the thickness of the media (R = 0.07) or the intima (R = 0.28) at the convex sample site. There was also no correlation of the ascending aortic diameter with age (R = −0.18) or body surface area (R = 0.07). The thickness of the intima (r = 0.31) and the media (R = 0.035) did not correlate with the Svensson index of aortic risk. Similarly, there was a low (R = 0.29) or absent (R = −0.04) correlation between the aortic size index and the intima or media thickness, respectively. There was a similar relationship of median thickness of the intima in the 4 aortic height index risk categories (P < 0.001). CONCLUSIONS Aortic diameter and conventional indices of aortic risk do not correlate with aortic wall thickness. Other indices may be required in order to identify patients at high risk for aortic complications.

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Features of Morphogenesis of Aortic Aneurysms on the Background of Hypertension and Associated Risk Factors

Ukrainian journal of cardiovascular surgery ◽

10.30702/ujcvs/21.4306/z022062-066/091.8 ◽

2021 ◽

pp. 62-66

Author(s):

V. Zakharova ◽

O. Rudenko ◽

V. Kravchenko

Keyword(s):

Risk Factors ◽

Aortic Aneurysm ◽

Aortic Wall ◽

Elevated Pressure ◽

Aortic Aneurysms ◽

Vasa Vasorum ◽

Morphological Examination ◽

Ascending Aortic Aneurysm ◽

The Media ◽

Associated Risk Factors

The aim. To investigate the role of hypertension and associated risk factors in the formation of aortic aneurysms. Material and methods. Retrospective analysis of 196 case histories of patients who were successively operated on for ascending aortic aneurysm at the National Amosov Institute of cardiovascular surgery. The history was analyzed, the duration and degree of hypertension were recorded, as well as other factors that may have influenced the development of ascending aortic aneurysm in some way. A pathomorphological examination of fragments of the aortic wall that were excised during the operation was performed. Out of all 294 examined patients operated for ascending aortic aneurysm, hypertension was reported in 196 (66.7%) patients. The incidence of ascending aortic aneurysm positively correlated with the duration of hypertension. The ma-jority of patients (118 [60.2%]) had signs of hypertension for more than five years. Additional ethiopathogenetic fac-tors were identified in patients with ascending aortic aneurysm and hypertension, with atherosclerosis ranking first (66 [33.6%]). The next factors that demonstrated the same incidence were the inflammatory process in the aorta and AV, and smoking: 45 cases each (22.9%). Then, in descending order, were: xenobiotics exposure (43 [21.9%]), rheumatic stenosis of AV (40 [20.4%]), chest injury (33 [16.8%]), dysplasia of AV (28 [14.3%]), alcohol abuse (13 [6.6%]), Marfan syndrome (9 [4.6%]), other (8 [4.1%]). The results of comparison of the history and pathomorphological findings allowed to develop a scheme of ascending aortic aneurysm pathogenesis in hypertension. The scheme of ascending aortic aneurysm pathogenesis in hypertension is discussed in the work. The results of morphological examination show that hypertension is associated with the dam-age to the aortic endothelium, which leads to fibromuscular proliferation of the intima with subsequent hypoxic damage to the inner layer of the media. Hypoxic damage to the media, which is associated with vasa vasorum remodeling due to hypertension, is also observed in the subventricular layer. Weakening of the aortic wall at elevated pressure causes dila-tation of the aorta, i.e. the formation of an aortic aneurysm. This process may be exacerbated by additional factors, with atherosclerosis being the most common (33.6%)

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MMP inhibition modulates TNF-α transgenic mouse phenotype early in the development of heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00233.2001 ◽

2002 ◽

Vol 282 (3) ◽

pp. H983-H989 ◽

Cited By ~ 44

Author(s):

Yun You Li ◽

Toshiaki Kadokami ◽

Ping Wang ◽

Charles F. McTiernan ◽

Arthur M. Feldman

Keyword(s):

Heart Failure ◽

Extracellular Matrix ◽

Critical Role ◽

Left Ventricular ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Insoluble Collagen ◽

Mmp Inhibitor ◽

Tnf Α ◽

And Function

Myocardial extracellular matrix remodeling regulated by matrix metalloproteinases (MMPs) is implicated in the progression of heart failure. We hypothesized that MMP inhibition may modulate extracellular matrix remodeling and prevent the progression of heart failure. The effects of the MMP inhibitor BB-94 (also known as batimastat) on MMP expression, collagen expression, collagen deposition, collagen denaturation, and left ventricular structure and function in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor-α (TNF-α) (TNF1.6) were assessed. The results showed that BB-94 reduced the expression of collagens, increased insoluble collagen and the ratio of undenatured to total soluble collagen, and prevented myocardial hypertrophy and diastolic dysfunction in young TNF1.6 mice. Furthermore, the treatment significantly improved cumulative survival of TNF1.6 mice. However, MMP inhibition did not have salutary effects on ventricular size and function in old mice with established heart failure. The results suggest that MMP activation may play a critical role in changes of myocardial function through the remodeling of extracellular matrix, and MMP inhibition may serve as a potential therapeutic strategy for heart failure, albeit within a narrow window during the development of heart failure.

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Biglycan expression and its function in human ligamentum flavum

Scientific Reports ◽

10.1038/s41598-021-84363-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hamidullah Salimi ◽

Akinobu Suzuki ◽

Hasibullah Habibi ◽

Kumi Orita ◽

Yusuke Hori ◽

...

Keyword(s):

Gene Expression ◽

Extracellular Matrix ◽

Cell Proliferation ◽

Cell Migration ◽

Cell Cultures ◽

Ligamentum Flavum ◽

Elastic Fibers ◽

Lumbar Spinal ◽

And Function ◽

Myofibroblastic Differentiation

AbstractHypertrophy of the ligamentum flavum (LF) is a major cause of lumbar spinal stenosis (LSS), and the pathology involves disruption of elastic fibers, fibrosis with increased cellularity and collagens, and/or calcification. Previous studies have implicated the increased expression of the proteoglycan family in hypertrophied LF. Furthermore, the gene expression profile in a rabbit experimental model of LF hypertrophy revealed that biglycan (BGN) is upregulated in hypertrophied LF by mechanical stress. However, the expression and function of BGN in human LF has not been well elucidated. To investigate the involvement of BGN in the pathomechanism of human ligamentum hypertrophy, first we confirmed increased expression of BGN by immunohistochemistry in the extracellular matrix of hypertrophied LF of LSS patients compared to LF without hypertrophy. Experiments using primary cell cultures revealed that BGN promoted cell proliferation. Furthermore, BGN induces changes in cell morphology and promotes myofibroblastic differentiation and cell migration. These effects are observed for both cells from hypertrophied and non-hypertrophied LF. The present study revealed hyper-expression of BGN in hypertrophied LF and function of increased proteoglycan in LF cells. BGN may play a crucial role in the pathophysiology of LF hypertrophy through cell proliferation, myofibroblastic differentiation, and cell migration.

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