scholarly journals A Novel Human Biospecimen Repository for Clinical and Molecular Investigation of Thoracic Aortopathy

2021 ◽  
Vol 11 (3) ◽  
pp. 148-163
Author(s):  
Courtney E. Vujakovich ◽  
Benjamin J. Landis
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Thoracic Aortic Aneurysm ◽  
Prognostic Markers ◽  
Aortic Tissue ◽  
Significant Morbidity ◽  
Aortic Smooth Muscle ◽  
Molecular Investigation ◽  
The Mean

Thoracic aortic aneurysm (TAA) is a heritable aortopathy with significant morbidity and mortality, affecting children and adults. Genetic causes, pathobiological mechanisms, and prognostic markers are incompletely understood. In 2015, the Collaborative Human Aortopathy Repository (CHAR) was created to address these fundamental gaps. Patients with thoracic aortopathy, associated genetic diagnoses, or aortic valve disease are eligible for prospective enrollment. Family members and controls are also enrolled. Detailed clinical and family data are collected, and blood and aortic tissue biospecimens are processed for broad usage. A total of 1047 participants were enrolled. The mean age in 834 affected participants was 47 ± 22 (range <1 to 88) years and 580 were male (70%). A total of 156 (19%) were under the age of 21 years. Connective tissue diagnoses such as Marfan syndrome were present in 123 (15%). Unaffected participants included relatives (N = 176) and healthy aorta tissue controls (N = 37). Aortic or aortic valve biospecimens were acquired from over 290 and 110 participants, respectively. RNA and protein were extracted from cultured aortic smooth muscle cells (SMCs) for 90 participants. Over 1000 aliquots of aortic SMCs were cryopreserved. The CHAR’s breadth, robust biospecimen processing, and phenotyping create a unique, multipronged resource to accelerate our understanding of human aortopathy.

Changes in vascular responsiveness following chronic exposure to cold in the rat

1983 ◽  
Vol 55 (3) ◽  
pp. 823-829 ◽  
Author(s):  
B. A. Bryar ◽  
M. J. Fregly ◽  
F. P. Field
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscles ◽  
Aortic Tissue ◽  
Adrenergic Stimulation ◽  
Beta Adrenergic ◽  
Aortic Smooth Muscle ◽  
Beta Adrenergic Agonists ◽  
Adrenergic Antagonist ◽  
Vascular Responsiveness ◽  
High Concentrations

The responsiveness of smooth muscle from rings of aortic tissue of cold-acclimated (CA, 6 degrees C, 5-15 wk) rats to both alpha- and beta-adrenergic agonists and KCl was tested and compared with that of warm-adapted (25 degrees C) controls. alpha-Adrenergic stimulation, induced by low doses (10(-8)-10(-7) M) of phenylephrine and norepinephrine in the presence and absence of the beta-adrenergic antagonist, propranolol, resulted in the development of less active tension by aortic smooth muscle from CA rats than from controls. Similar results were observed with the weakly alpha 1-adrenergic agonistic activities of tyramine, clonidine, and high concentrations of isoproterenol (10(-6)-10(-4) M). There was also a significant reduction in the tension developed by smooth muscles of the aortas from CA rats when depolarized with KCl in concentrations ranging from 8 to 20 mM. In contrast, aortic smooth muscle, contracted to 75% of maximum with KCl, showed an enhanced relaxation to the beta-adrenergic agonist, isoproterenol, in CA rats. These studies suggest that acclimation of rats to cold results in both a decrease in alpha-adrenergic responsiveness and an increase in beta-adrenergic responsiveness in vascular smooth muscle as well as a change in the biochemical events that couple activation of adrenergic receptors to changes in vasomotor tone.

Potent inhibition of the aortic smooth muscle maxi-K channel by clinical doses of ethanol

2000 ◽  
Vol 279 (4) ◽  
pp. C1107-C1115 ◽  
Author(s):  
F. S. Walters ◽  
M. Covarrubias ◽  
J. S. Ellingson
Keyword(s):  
Smooth Muscle ◽  
Lipid Bilayers ◽  
Single Channel ◽  
K Channel ◽  
Open Probability ◽  
K Channels ◽  
Aortic Smooth Muscle ◽  
Slope Factor ◽  
The Mean ◽  
Relationship Change

We investigated the effects of clinically relevant ethanol concentrations (5–20 mM) on the single-channel kinetics of bovine aortic smooth muscle maxi-K channels reconstituted in lipid bilayers (1:1 palmitoyl-oleoyl-phosphatidylethanolamine: palmitoyl-oleoyl-phosphatidylcholine). Ethanol at 10 and 20 mM decreased the channel open probability ( P o) by 75 ± 20.3% mainly by increasing the mean closed time (+82 to +960%, n = 7). In some instances, ethanol also decreased the mean open time (−40.8 ± 22.5%). The P o-voltage relation in the presence of 20 mM ethanol exhibited a rightward shift in the midpoint of voltage activation (Δ V ½ ≅ 17 mV), a slightly steeper relationship (change in slope factor, Δ k, ≅ −2.5 mV), and a decreased maximum P o (from ∼0.82 to ∼0.47). Interestingly, channels inhibited by ethanol at low Ca2+ concentrations (2.5 μM) were very resistant to ethanol in the presence of increased Ca2+ (≥ 20 μM). Alcohol consumption in clinically relevant amounts may alter the contribution of maxi-K channels to the regulation of arterial tone.

Abstract 397: Analysis of Cell Phenotype in Relation to TGFβ Treatment of Aortic Smooth Muscle Cells and Myofibroblasts Isolated from Aortas and Valves of Thoracic Aortic Aneurysm Patients with a Tricuspid or a Bicuspid Valve

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Valentina Paloschi ◽  
Lasse Folkersen ◽  
Sanela Kurtovic ◽  
Dick Wagsater ◽  
Anders Franco Cereceda ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Thoracic Aortic Aneurysm ◽  
Muscle Cells ◽  
Cell Types ◽  
Cell Phenotype ◽  
Matrix Remodeling ◽  
Exon Arrays

Background Thoracic aortic aneurysm (TAA) is a pathological widening of the aorta, due to degeneration of extracellular matrix (ECM) and loss of smooth muscle cells (SMCs). Bicuspid aortic valve (BAV) is a congenital disorder present in 1-2 % of the population which makes TAA associated with BAV a common complication. Previously we showed that aortas isolated from BAV and normal tricuspid aortic valve (TAV) patients are different both at gene and protein levels. Particularly, differences in the TGFβ pathway seem to be crucial players in aneurysm development, affecting matrix remodeling and wound healing. Since SMCs and myofibroblasts are the critical cells responsible for these activities, we evaluated different properties of the cells focusing on fibronectin (FN) and its spliced versions, a target gene of TGFβ. Interestingly, extra domain A of FN (EDA) was previously described for its roles in vascular morphogenesis, as well as in processes like migration and proliferation. Methods and results Biopsies from the thoracic aorta and Aortic valves were collected during Elective Aortic Valve Replacement Surgery. mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=46) and BAV (n=77). Expression of EDA was found increased only in dilated aortas from TAV patients but not in BAV patients. Primary SMCs were isolated with the explant outgrowth technique from aortas of BAV and TAV patients (n=15). Myofibroblasts were isolated by collagenase digestion from BAV and TAV valves (n=30). Cells were cultured and treated with TGFβ at a concentration of 20 ng/ml for 6h. TGFβ treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in SMCs from TAV patients but not in cells derived from BAV patients. We have not observed clear differences in SMC proliferation and migration. Myofibrolasts analysis is ongoing. Conclusions So far, our results suggest that despite a decreased EDA-fibronectin expression in BAV cells, the phenotype of SMCs isolated from BAV and TAV patients in culture does not differ. However, impaired TGFβ signaling that may result in the increased susceptibility of BAV patients to develop TAA could be due to effects on other cell types.

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