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Cell Death & Disease Nov 2023Phenotypic and functional changes in vascular smooth muscle cells (VSMCs) contribute significantly to cardiovascular diseases (CVD) but factors driving early adverse...
Phenotypic and functional changes in vascular smooth muscle cells (VSMCs) contribute significantly to cardiovascular diseases (CVD) but factors driving early adverse vascular changes are poorly understood. We report on novel and important roles for the Brn-3b/POU4F2 (Brn-3b) transcription factor (TF) in controlling VSMC integrity and function. Brn-3b protein is expressed in mouse aorta with localisation to VSMCs. Male Brn-3b knock-out (KO) aortas displayed extensive remodelling with increased extracellular matrix (ECM) deposition, elastin fibre disruption and small but consistent narrowing/coarctation in the descending aortas. RNA sequencing analysis showed that these effects were linked to deregulation of genes required for calcium (Ca) signalling, vascular contractility, sarco-endoplasmic reticulum (S/ER) stress responses and immune function in Brn-3b KO aortas and validation studies confirmed changes in Ca signalling genes linked to increased intracellular Ca and S/ER Ca depletion [e.g. increased, Cacna1d Ca channels; ryanodine receptor 2, (RyR2) and phospholamban (PLN) but reduced ATP2a1, encoding SERCA1 pump] and chaperone proteins, Hspb1, HspA8, DnaJa1 linked to increased S/ER stress, which also contributes to contractile dysfunction. Accordingly, vascular rings from Brn-3b KO aortas displayed attenuated contractility in response to KCl or phenylephrine (PE) while Brn-3b KO-derived VSMC displayed abnormal Ca signalling following ATP stimulation. This data suggests that Brn-3b target genes are necessary to maintain vascular integrity /contractile function and deregulation upon loss of Brn-3b will contribute to contractile dysfunction linked to CVD.
Topics: Animals; Male; Mice; Aorta; Calcium; Cardiovascular Diseases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Transcription Factor Brn-3B
PubMed: 38007517
DOI: 10.1038/s41419-023-06306-w -
Acta Biomaterialia Feb 2020Aortic mechanical and structural characteristics have profound effects on pathophysiology, but many aspects of physiologic stress-stretch state and intramural changes...
Aortic mechanical and structural characteristics have profound effects on pathophysiology, but many aspects of physiologic stress-stretch state and intramural changes due to aging remain poorly understood in human tissues. While difficult to assess in vivo due to residual stresses and pre-stretch, physiologic stress-stretch characteristics can be calculated using experimentally-measured mechanical properties and constitutive modeling. Mechanical properties of 76 human descending thoracic aortas (TA) from 13 to 78-year-old donors (mean age 51±18 years) were measured using multi-ratio planar biaxial extension. Constitutive parameters were derived for aortas in 7 age groups, and the physiologic stress-stretch state was calculated. Intramural characteristics were quantified from histological images and related to aortic morphometry and mechanics. TA stiffness increased with age, and aortas became more nonlinear and anisotropic. Systolic and diastolic elastic energy available for pulsation decreased with age from 30 to 8 kPa and from 18 to 5 kPa, respectively. Cardiac cycle circumferential stretch dropped from 1.14 to 1.04, and circumferential and longitudinal physiologic stresses decreased with age from 90 to 72 kPa and from 90 to 17 kPa, respectively. Aortic wall thickness and radii increased with age, while the density of elastin in the tunica media decreased. The number of elastic lamellae and circumferential physiologic stress per lamellae unit remained constant with age at 102±10 and 0.85±0.04 kPa, respectively. Characterization of mechanical, physiological, and structural features in human aortas of different ages can help understand aortic pathology, inform the development of animal models that simulate human aging, and assist with designing devices for open and endovascular aortic repairs. STATEMENT OF SIGNIFICANCE: This manuscript describes mechanical and structural changes occurring in human thoracic aortas with age, and presents material parameters for 4 commonly used constitutive models. Presented data can help better understand aortic pathology, inform the development of animal models that simulate human aging, and assist with designing devices for open and endovascular aortic repairs.
Topics: Adolescent; Adult; Aged; Aging; Aorta, Thoracic; Biomechanical Phenomena; Elasticity; Female; Humans; Male; Middle Aged; Risk Factors; Stress, Mechanical; Young Adult
PubMed: 31877371
DOI: 10.1016/j.actbio.2019.12.024 -
Cell and Tissue Banking Sep 2018The aims of this study were to develop a biological large diameter vascular graft by decellularisation of native human aorta to remove the immunogenic cells whilst...
The aims of this study were to develop a biological large diameter vascular graft by decellularisation of native human aorta to remove the immunogenic cells whilst retaining the essential biomechanical, and biochemical properties for the ultimate benefit of patients with infected synthetic grafts. Donor aortas (n = 6) were subjected to an adaptation of a propriety decellularisation process to remove the cells and acellularity assessed by histological analysis and extraction and quantification of total DNA. The biocompatibility of the acellular aortas was determined using standard contact cytotoxicity tests. Collagen and denatured collagen content of aortas was determined and immunohistochemistry was used to determine the presence of specific extracellular matrix proteins. Donor aortas (n = 6) were divided into two, with one half subject to decellularisation and the other half retained as native tissue. The native and decellularised aorta sections were then subject to uniaxial tensile testing to failure [axial and circumferential directions] and suture retention testing. The data was compared using a paired t-test. Histological evaluation showed an absence of cells in the treated aortas and retention of histoarchitecture including elastin content. The decellularised aortas had less than 15 ng mg total DNA per dry weight (mean 94% reduction) and were biocompatible as determined by in vitro contact cytotoxicity tests. There were no gross changes in the histoarchitecture [elastin and collagen matrix] of the acellular aortas compared to native controls. The decellularisation process also reduced calcium deposits within the tissue. The uniaxial tensile and suture retention testing revealed no significant differences in the material properties (p > 0.05) of decellularised aorta. The decellularisation procedure resulted in minimal changes to the biological and biomechanical properties of the donor aortas. Acellular donor aorta has excellent potential for use as a large diameter vascular graft.
Topics: A549 Cells; Aorta; Biocompatible Materials; Biomechanical Phenomena; Bioprosthesis; Blood Vessel Prosthesis; Collagen; DNA; Extracellular Matrix; Humans; Materials Testing; Tensile Strength; Tissue Engineering; Tissue Scaffolds
PubMed: 29188402
DOI: 10.1007/s10561-017-9673-y -
Proteomics. Clinical Applications Apr 2013Evaluate combination of heat and elevated pressure to enhance protein extraction and quality of formalin-fixed (FF), and FF paraffin-embedded (FFPE) aorta for proteomics.
PURPOSE
Evaluate combination of heat and elevated pressure to enhance protein extraction and quality of formalin-fixed (FF), and FF paraffin-embedded (FFPE) aorta for proteomics.
EXPERIMENT DESIGN
Proteins were extracted from fresh frozen aorta at room temperature (RT). FF and FFPE aortas (3 months and 15 years) were extracted at RT, heat alone, or a combination of heat and high pressure. Protein yields were compared, and digested peptides from the extracts were analyzed with MS.
RESULTS
Combined heat and elevated pressure increased protein yield from human FF or FFPE aorta compared to matched tissues with heat alone (1.5-fold) or at RT (8.3-fold), resulting in more proteins identified and with more sequence coverage. The length of storage did adversely affect the quality of proteins from FF tissue. For long-term storage, aorta was preserved better with FFPE than FF alone. Periostin and MGF-E8 were demonstrated suitable for MRM assays from FFPE aorta.
CONCLUSIONS AND CLINICAL RELEVANCE
Combination of heat and high pressure is an effective method to extract proteins from FFPE aorta for downstream proteomics. This method opens the possibility for use of archival and often rare FFPE aortas and possibly other tissues available to proteomics for biomarker discovery and quantification.
Topics: Aorta; Biomarkers; Fixatives; Formaldehyde; Humans; Paraffin; Paraffin Embedding; Proteins; Proteomics; Tissue Fixation
PubMed: 23339088
DOI: 10.1002/prca.201200064 -
Scientific Reports Jul 2021The aim was to evaluate the thoracic aorta in different cardiac phases to obtain the correct cardiac phase for measuring the maximum diameter required to predict aortic...
The aim was to evaluate the thoracic aorta in different cardiac phases to obtain the correct cardiac phase for measuring the maximum diameter required to predict aortic disease. Cardiac CT was performed on 97 patients for suspected coronary artery disease. The average diameter of ascending (AAD) and descending aorta (DAD) in the plane of pulmonary bifurcation, in the plane of the sinus junction (AAD [STJ] and DAD [STJ]), descending aorta in the plane of the diaphragm (DAD [Dia]), the diameter of the main pulmonary artery (MPAD), distance from the sternum to the spine (S-SD), and distance from the sternum to the ascending aorta (S-AAD) were assessed at 20 different time points in the cardiac cycle. Differences in aortic diameter in different cardiac phases and the correlation between aortic diameter and traditional risk factors were analyzed by the general linear mixed model. The diameter of the thoracic aorta reached the minimum at the phase of 95-0%, and reached the maximum at 30-35%. The maximum values of AAD, AAD (STJ), DAD, DAD (STJ), and DAD (Dia) were 32.51 ± 3.35 mm, 28.86 ± 3.01 mm, 23.46 ± 2.88 mm, 21.85 ± 2.58 mm, and 21.09 ± 2.66 mm, respectively. The maximum values of MPAD/AAD and DAD/AAD (STJ) were 0.8140 ± 0.1029, 0.7623 ± 0.0799, respectively. The diameter of the thoracic aorta varies with the cardiac phase. Analyzing the changes in aortic diameter, which can be done using cardiac CT, could provide a more accurate clinical measurement for predicting aortic disease.
Topics: Adult; Aorta, Thoracic; Cardiac Imaging Techniques; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Tomography, X-Ray Computed
PubMed: 34312448
DOI: 10.1038/s41598-021-94677-5 -
Biomolecules Feb 2022Aortic aneurysms and dissections are life-threatening conditions that have a high risk for lethal bleeding and organ malperfusion. Many studies have investigated the... (Review)
Review
Aortic aneurysms and dissections are life-threatening conditions that have a high risk for lethal bleeding and organ malperfusion. Many studies have investigated the molecular basis of these diseases using mouse models. In mice, ex vivo, in situ, and ultrasound imaging are major approaches to evaluate aortic diameters, a common parameter to determine the severity of aortic aneurysms. However, accurate evaluations of aortic dimensions by these imaging approaches could be challenging due to pathological features of aortic aneurysms. Currently, there is no standardized mode to assess aortic dissections in mice. It is important to understand the characteristics of each approach for reliable evaluation of aortic dilatations. In this review, we summarize imaging techniques used for aortic visualization in recent mouse studies and discuss their pros and cons. We also provide suggestions to facilitate the visualization of mouse aortas.
Topics: Aortic Dissection; Animals; Aorta; Aortic Aneurysm; Disease Models, Animal; Mice; Ultrasonography
PubMed: 35204838
DOI: 10.3390/biom12020339 -
Scientific Reports Apr 2021All blood cells originate from hematopoietic stem/progenitor cells (HSPCs). HSPCs are formed from endothelial cells (ECs) of the dorsal aorta (DA), via...
All blood cells originate from hematopoietic stem/progenitor cells (HSPCs). HSPCs are formed from endothelial cells (ECs) of the dorsal aorta (DA), via endothelial-to-hematopoietic transition (EHT). The zebrafish is a primary model organism to study the process in vivo. While the role of mechanical stress in controlling gene expression promoting cell differentiation is actively investigated, mechanisms driving shape changes of the DA and individual ECs remain poorly understood. We address this problem by developing a new DA micromechanical model and applying it to experimental data on zebrafish morphogenesis. The model considers the DA as an isotropic tubular membrane subjected to hydrostatic blood pressure and axial stress. The DA evolution is described as a movement in the dimensionless controlling parameters space: normalized hydrostatic pressure and axial stress. We argue that HSPC production is accompanied by two mechanical instabilities arising in the system due to the plane stress in the DA walls and show how a complex interplay between mechanical forces in the system drives the emerging morphological changes.
Topics: Animals; Aorta; Hematopoiesis; Hematopoietic Stem Cells; Models, Cardiovascular; Stress, Mechanical; Time-Lapse Imaging; Zebrafish
PubMed: 33927284
DOI: 10.1038/s41598-021-88667-w -
The Journal of Trauma and Acute Care... Aug 2021Noncompressible hemorrhage is a leading cause of preventable death in civilian and military trauma populations. Resuscitative endovascular balloon occlusion of the aorta...
BACKGROUND
Noncompressible hemorrhage is a leading cause of preventable death in civilian and military trauma populations. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a promising method for controlling noncompressible hemorrhage, but safe balloon inflation parameters are not well defined. Our goal was to determine the balloon inflation parameters associated with benchtop flow occlusion and aortic/balloon rupture in ex vivo human aortas and test the hypothesis that optimal balloon inflation characteristics depend on systolic pressure and subject demographics.
METHODS
Aortic occlusion parameters in human thoracic aortas (TAs) and abdominal aortas (AAs) from 79 tissue donors (median ± SD age, 52 ± 18 years [range, 13-75 years]; male, 52; female, 27) were recorded under 100/40, 150/40, and 200/40 mm Hg flow pressures for ER-REBOA and Coda balloons. Rupture tests were done with Coda balloons only without flow.
RESULTS
In the TA, the average balloon inflation volumes and pressures resulting in 100/40 mm Hg flow occlusion were 11.7 ± 3.8 mL and 174 ± 65 mm Hg for the ER-REBOA, and 10.6 ± 4.3 mL and 94 ± 57 mm Hg for the Coda balloons. In the AA, these values were 6.2 ± 2.6 mL and 110 ± 47 mm Hg for the ER-REBOA, and 5.9 ± 2.2 mL and 71 ± 30 mm Hg for the Coda. The average balloon inflation parameters associated with aortic/Coda balloon rupture were 39.1 ± 6.5 mL and 1,284 ± 385 mm Hg in the TA, and 27.7 ± 7.7 mL and 1,410 ± 483 mm Hg in the AA. Age, sex, and systolic pressure all had significant effects on balloon occlusion and rupture parameters.
CONCLUSION
Optimal balloon inflation parameters depend on anatomical, physiological, and demographic characteristics. Pressure-guided rather than volume-guided balloon inflation may reduce the risk of aortic rupture. These results can be used to help improve the safety of REBOA procedures and devices.
Topics: Adolescent; Adult; Aged; Aorta, Abdominal; Aorta, Thoracic; Balloon Occlusion; Endovascular Procedures; Female; Hemorrhage; Humans; Male; Middle Aged; Resuscitation; Young Adult
PubMed: 34039932
DOI: 10.1097/TA.0000000000003276 -
The Journal of Thoracic and... Jan 2007The residual aorta's behavior after repair of acute type A dissection is incompletely understood. We analyzed segmental growth rates, distal reoperation, and factors...
OBJECTIVES
The residual aorta's behavior after repair of acute type A dissection is incompletely understood. We analyzed segmental growth rates, distal reoperation, and factors influencing long-term survival.
METHODS
One hundred seventy-nine consecutive patients (70% male; mean age, 60 years) with acute type A dissection underwent aggressive resection of the intimal tear and open distal anastomosis (1986-2003). Hospital mortality was 13.4%. Survivors had serial computed tomographic scans: digitization yielded distal segmental dimensions. Segment-specific average rates of enlargement and factors influencing faster growth were analyzed. Distal reoperations and patient survival were examined.
RESULTS
Eighty-nine (57%) patients had imaging data sufficient for growth rate calculations. The median diameters after repair were as follows: aortic arch, 3.6 cm; descending aorta, 3.7 cm; and abdominal aorta, 3.2 cm. Subsequent growth rates were 0.8, 1.0, and 0.8 mm/y, respectively. Initial size of greater than 4 cm (P = .005) and initial diameter of less than 4 cm with a patent false lumen (P = .004) predicted greater growth in the descending aorta, and male sex (P = .05) significantly affected growth in the abdominal aorta. No significant factors were found for the aortic arch. There were 25 distal aortic reoperations (16 patients), and risk of reoperation was 16% at 10 years. Risk factors reducing long-term survival after repair of acute type A dissection included age (P < .0001), new neurological deficit at presentation (P = .04), absence of preoperative thrombus in the false lumen of the ascending aorta (P = .03), and a patent distal false lumen postoperatively (P = .06) but not distal reoperation.
CONCLUSIONS
Growth of the distal aorta after repair of acute type A dissection is typically slow and linear. Distal reoperation is uncommon, and late risk of death is approximately twice that of a healthy population.
Topics: Acute Disease; Aortic Dissection; Aorta; Aortic Aneurysm; Blood Vessel Prosthesis Implantation; Female; Hospital Mortality; Humans; Male; Middle Aged; Proportional Hazards Models; Survival Rate
PubMed: 17198797
DOI: 10.1016/j.jtcvs.2006.07.043 -
Journal of Smooth Muscle Research =... 2022This study aimed to verify whether Adjuvant-Induced Arthritis (AIA) and/or Orchiectomy (ORX) modify the expression of the Nox1, Nox2 and Nox4 isoforms, the endothelial...
PURPOSE
This study aimed to verify whether Adjuvant-Induced Arthritis (AIA) and/or Orchiectomy (ORX) modify the expression of the Nox1, Nox2 and Nox4 isoforms, the endothelial function or the structure of rat aortas.
METHODS
Sixty-three Wistar rats were distributed into four groups: 1) Control; 2) ORX; 3) AIA; 4) Orchiectomy plus to Arthritis-induction (ORX/AIA). Thus, 21 days after the onset of AIA (by intradermal injection of Mycobacterium tuberculosis), the presence of Nox1, Nox2 and Nox4, the acetylcholine (ACh)-induced relaxation and the media layer thickness were assessed in the aorta taken from these animals.
RESULTS
The Nox1, Nox2 and Nox4 were immunostained in intima, media and adventitia layers of aortas taken from all studied groups and AIA apparently increased this immunostaining. These modifications of Nox1, Nox2 or Nox4 expression, however, were not confirmed by Western blotting. In addition, neither AIA nor ORX changed the endothelial function, but ORX increased the media layer thickness in the studied aortas.
CONCLUSION
The present study showed weak clues of increased expression of Nox1, Nox2 and Nox4 as a result of AIA, as well as of Nox1 reduction caused by ORX. In addition, the endothelial function was not modified in the aortas of these animals by both AIA and/or ORX. On the other hand, ORX increased significantly the aorta media layer thickness in the studied animals, which was apparently mitigated by AIA.
Topics: Animals; Aorta; Arthritis, Experimental; Endothelium, Vascular; Male; Orchiectomy; Rats; Rats, Wistar
PubMed: 35944980
DOI: 10.1540/jsmr.58.63