Aortic Hemodynamics and Endothelial Gene Expression: An Animal Specific Approach

2011 ◽  
Author(s):  
Yi Chung Lim ◽  
David S. Long
Keyword(s):  
Cell Layer ◽  
Mechanical Stresses ◽  
Cell Phenotype ◽  
Atherosclerotic Lesions ◽  
Dynamic Cell ◽  
Flowing Blood ◽  
Endothelial Gene Expression ◽  
Developed World ◽  
Accumulation Of Lipids ◽  
Aortic Hemodynamics

Atherosclerosis is a major cause of morbidity and mortality in the developed world. This disease is identified by endothelial dysfunction, inflammation and the accumulation of lipids and cellular elements within the intima of medium and large-sized arteries. Within these arteries, the distribution of atherosclerotic lesions is non-uniform; the inner wall of curved sections and the outer walls of bifurcations are susceptible sites. Evidence suggests that the focal nature of the disease is mediated in part by local fluid mechanical stresses at the interface between flowing blood and the vessel wall. Strategically located at this interface is the monolayer of cells known as the endothelium. Although it was once considered to be an inert cell layer, the endothelium is a highly complex and metabolically dynamic cell layer. As a result, local fluid mechanical stresses at the wall of arteries may alter the phenotype of endothelial cells (ECs). With that in mind, the aim of this study is to better characterize the modulation of the endothelial cell phenotype in response to blood flow induced wall shear stress (WSS).

Quantifying the Motion of Murine Epicardial Coronary Arteries

2008 ◽  
Author(s):  
David S. Long ◽  
Hui Zhu ◽  
Morton H. Friedman
Keyword(s):  
Risk Factors ◽  
Coronary Arteries ◽  
Mechanical Stresses ◽  
Intimal Thickening ◽  
High Cholesterol ◽  
Additional Risk ◽  
Atherosclerotic Lesions ◽  
Coronary Artery Atherosclerosis ◽  
Obesity Hypertension ◽  
Accumulation Of Lipids

Coronary artery atherosclerosis is a leading cause of morbidity and mortality in western societies. Atherosclerosis is a progressive fibroinflammatory disease identified by intimal thickening, the focal accumulation of lipids, fibrous elements, and cellular elements within the walls of large arteries. These lesions preferentially develop at arterial branches, the outer walls of bifurcations, and the inner walls of curved sections; the cause of this focal vasculopathy is not fully understood. It is, however, understood from epidemiological and clinical studies that individual susceptibility to the development and progression of atherosclerotic lesions is influenced by “traditional” systemic risk factors, including smoking, diabetes mellitus, obesity, hypertension, and high cholesterol. However, these risk factors cannot account for half of the variability in occurrence of this disease; this indicates additional risk factors have not been identified. One prevalent explanation of the focal nature of the disease is that the local fluid mechanical stresses at the walls of coronary arteries, as well as mechanical stresses within the vessel wall, may mediate the phenotype of endothelial cells thereby producing atherosusceptible sites. Therefore, it has been speculated [1] that certain aspects of arterial geometry and motion, which vary substantially among individuals, may increase an individual’s susceptibility to developing atherosclerosis — “geometric risk factors”.

scholarly journals Stem Cell Pluripotency Genes Klf4 and Oct4 Regulate Complex SMC Phenotypic Changes Critical in Late-Stage Atherosclerotic Lesion Pathogenesis

Circulation ◽  
2020 ◽  
Vol 142 (21) ◽  
pp. 2045-2059 ◽  
Author(s):  
Gabriel F. Alencar ◽  
Katherine M. Owsiany ◽  
Santosh Karnewar ◽  
Katyayani Sukhavasi ◽  
Giuseppe Mocci ◽  
...  
Keyword(s):  
Stem Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Late Stage ◽  
Lineage Tracing ◽  
Stem Cell Marker ◽  
Cell Phenotype ◽  
Phenotypic Changes ◽  
Atherosclerotic Lesions ◽  
Single Cell Rna Sequencing

Background: Rupture and erosion of advanced atherosclerotic lesions with a resultant myocardial infarction or stroke are the leading worldwide cause of death. However, we have a limited understanding of the identity, origin, and function of many cells that make up late-stage atherosclerotic lesions, as well as the mechanisms by which they control plaque stability. Methods: We conducted a comprehensive single-cell RNA sequencing of advanced human carotid endarterectomy samples and compared these with single-cell RNA sequencing from murine microdissected advanced atherosclerotic lesions with smooth muscle cell (SMC) and endothelial lineage tracing to survey all plaque cell types and rigorously determine their origin. We further used chromatin immunoprecipitation sequencing (ChIP-seq), bulk RNA sequencing, and an innovative dual lineage tracing mouse to understand the mechanism by which SMC phenotypic transitions affect lesion pathogenesis. Results: We provide evidence that SMC-specific Klf4- versus Oct4-knockout showed virtually opposite genomic signatures, and their putative target genes play an important role regulating SMC phenotypic changes. Single-cell RNA sequencing revealed remarkable similarity of transcriptomic clusters between mouse and human lesions and extensive plasticity of SMC- and endothelial cell-derived cells including 7 distinct clusters, most negative for traditional markers. In particular, SMC contributed to a Myh11 - , Lgals3 + population with a chondrocyte-like gene signature that was markedly reduced with SMC- Klf4 knockout. We observed that SMCs that activate Lgals3 compose up to two thirds of all SMC in lesions. However, initial activation of Lgals3 in these cells does not represent conversion to a terminally differentiated state, but rather represents transition of these cells to a unique stem cell marker gene–positive, extracellular matrix-remodeling, “pioneer” cell phenotype that is the first to invest within lesions and subsequently gives rise to at least 3 other SMC phenotypes within advanced lesions, including Klf4-dependent osteogenic phenotypes likely to contribute to plaque calcification and plaque destabilization. Conclusions: Taken together, these results provide evidence that SMC-derived cells within advanced mouse and human atherosclerotic lesions exhibit far greater phenotypic plasticity than generally believed, with Klf4 regulating transition to multiple phenotypes including Lgals3 + osteogenic cells likely to be detrimental for late-stage atherosclerosis plaque pathogenesis.

Platelets Provide Signals for CD34+ Progenitor Cells to Home to Sites of Vascular Injury.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2679-2679
Author(s):  
Anton Jan Van Zonneveld ◽  
Caroline Verseyden ◽  
Cindy J.M. Loomans ◽  
Ton J. Rabelink ◽  
Hetty C. De Boer
Keyword(s):  
Progenitor Cells ◽  
Vascular Injury ◽  
Vascular Function ◽  
Transforming Growth Factor ◽  
Coagulation System ◽  
Cell Phenotype ◽  
Boyden Chamber ◽  
Vegf Receptor ◽  
Cd34 Cells ◽  
Flowing Blood

Abstract Introduction Accumulating evidence indicates that vascular function is modulated by circulating progenitor cells (PCs). Circulating PCs have been shown to enhance angiogenesis, promote vascular repair, improve endothelial function, inhibit atherosclerosis and increase ventricular function after myocardial infarction. How circulating PCs home to their target sites is not known. Hypothesis Since vascular damage, ischemia and atherosclerosis coincides with the activation of coagulation and platelets we hypothesized that fibrin, activated platelets and platelet products might trigger circulating PCs to home to sites of injury. Homing involves (1) escape of PCs from flowing blood, (2) migration towards an injury and (3) differentiation into an endothelial cell phenotype. Methods & Results (1) Escape from flowing blood was tested in a flow model using tissue factor expressing endothelial cells (ECs) on which a fibrin network containing thrombi was formed under flow. The platelet thrombi offered flowing CD34+ cells a landing site leading to deceleration and firm attachment to the surrounding ECs. Tethering of the CD34+ was dependent on P-Selectin expressed by the platelets, since blokkage of P-Selectin or P-Selectin glycoprotein ligand-1, expressed by the CD34+, prevented deceleration of the CD34+ cells. (2) Migration of PCs was tested in a Boyden chamber in which fibrin, fibrin+platelets or platelets alone was used to attract CD34+ cells. Fibrin+platelets induced migration of CD34+ cells, while fibrin or platelets had no effect. (3) Differentiation of PCs was tested in a culture system using a fibrin clot containing platelets and a culture medium lacking serum and additional growth factors. In this way, secreted platelet products like VEGF, transforming growth factor, platelet activating factor or lysophosphatidic acid determine the culture conditions. After 10 days of culture on fibrin+platelets, CD34+ PCs showed uptake of acetylated LDL, expression of eNOS, VEGF receptor 2 and CD31, indicating that the cells exhibited endothelial-like features. Conclusion Our results indicate that activation of the coagulation system and consequently activation of platelets, may offer circulating PCs a way to efficiently home to sites of vascular injury and thus contribute to neovascularization.

scholarly journals Fatty Acid Metabolism Disorder as a Factor in Atherogenesis

2018 ◽  
Vol 25 (3) ◽  
pp. 243-252
Author(s):  
Alexander N. Osipenko
Keyword(s):  
Fatty Acid ◽  
Blood Plasma ◽  
Vascular Wall ◽  
Plasma Lipoproteins ◽  
Vascular Lesions ◽  
Metabolism Disorder ◽  
Atherosclerotic Lesions ◽  
Fatty Acid Synthases ◽  
Accumulation Of Lipids ◽  
Increased Activity

Abstract Background and aims: The study aims to analyze of fatty acid (FA) composition of arteries and blood plasma in atherosclerosis. Material and method: The blood plasma in patients with coronary atherosclerosis was studied, the blood from healthy volunteers was used as control. There were also analyzed arteries of patients with severe atherosclerotic lesions and arteries of people with significantly less atherosclerotic changes. Results: The received data indicates that there is a rather active penetration of FA from blood plasma lipoproteins into intima of arteries. Penetration of FA from blood lipoproteins into the depth of atherosclerotic aorta and an atherosclerotic plaque appears to be small and does not effect on their fatty acid composition, which is similar to that of free FA of blood plasma. The evidence of the increased activity of desaturases and fatty acid synthases in atherosclerotic and intact arteries in patients with severe atherosclerotic vascular lesions was obtained. This increase in activity may be related by relatively low content of polyunsaturated linoleic acid in blood plasma in atherosclerosis. Conclusions: The increased activity of desaturases and fatty acid synthases as well as arterial wall hypoxia must promote accumulation of lipids in vascular wall by increasing the synthesis and inhibition of FA oxidation including free FA coming from blood.

scholarly journals The Atherogenic Role of Circulating Modified Lipids in Atherosclerosis

2019 ◽  
Vol 20 (14) ◽  
pp. 3561 ◽  
Author(s):  
Summerhill ◽  
Grechko ◽  
Yet ◽  
Sobenin ◽  
Orekhov
Keyword(s):  
Immune Complexes ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Diagnostic Biomarkers ◽  
Modified Ldl ◽  
Atherosclerotic Lesions ◽  
Ldl Particles ◽  
Atherosclerosis Development ◽  
Accumulation Of Lipids

Lipid accumulation in the arterial wall is a crucial event in the development of atherosclerotic lesions. Circulating low-density lipoprotein (LDL) is the major source of lipids that accumulate in the atherosclerotic plaques. It was discovered that not all LDL is atherogenic. In the blood plasma of atherosclerotic patients, LDL particles are the subject of multiple enzymatic and non-enzymatic modifications that determine their atherogenicity. Desialylation is the primary and the most important atherogenic LDL modification followed by a cascade of other modifications that also increase blood atherogenicity. The enzyme trans-sialidase is responsible for the desialylation of LDL, therefore, its activity plays an important role in atherosclerosis development. Moreover, circulating modified LDL is associated with immune complexes that also have a strong atherogenic potential. Moreover, it was shown that antibodies to modified LDL are also atherogenic. The properties of modified LDL were described, and the strong evidence indicating that it is capable of inducing intracellular accumulation of lipids was presented. The accumulated evidence indicated that the molecular properties of modified LDL, including LDL-containing immune complexes can serve as the prognostic/diagnostic biomarkers and molecular targets for the development of anti-atherosclerotic drugs.

scholarly journals Ablation of SAMD1 in Mice Causes Failure of Angiogenesis, Embryonic Lethality

2022 ◽  
Author(s):  
Bruce Campbell ◽  
Sandra Engle ◽  
Patricia Bourassa ◽  
Robert Aiello
Keyword(s):  
Blood Cells ◽  
Normal Function ◽  
Cell Phenotype ◽  
Fab Fragment ◽  
Sterile Alpha Motif Domain ◽  
Atherosclerotic Lesions ◽  
Embryonic Lethal ◽  
Carotid Injury ◽  
Ldl Binding ◽  
Injury Models

Pathological retention of LDL in the intima is involved in atherosclerosis, although the retention mechanisms are not well-understood. Previously, we reported Sterile Alpha Motif Domain Containing 1 (SAMD1), a protein secreted by intimal smooth muscle cells in atherosclerotic lesions, appears to bind LDL in extracellular matrix around intimal cells. Fab-fragment inhibitors of apparently irreversible SAMD1/LDL binding reduced LDL retention in carotid injury models, but did not have a significant effect on early spontaneous lesion initiation. The normal function of SAMD1 is unknown, but it may have multiple epigenetic roles; our histology of mouse atherosclerosis models revealed extensive SAMD1 expression, possibly related to cell phenotype modulation and antigen presentation. For this report, we generated SAMD1-/-, SAMD1-/+, and SAMD1-/+ apoE-/- mice to further explore SAMD1's role in atherosclerosis. SAMD1 was found in tissues throughout the SAMD1+/+ and SAMD1-/+embryos. Homozygous loss of SAMD1 was embryonic lethal: at embryonic day 14, organs were partially developed and/or degraded; heads and brains were malformed; no blood vessels were observed; red blood cells were scattered and pooled, primarily near the embryo surface; and cell death was occurring. Development appeared normal in heterozygous SAMD1 embryos, but postnatal genotyping showed a reduced ability to thrive. Growth of atherosclerotic lesions in SAMD1-/+ apoE-/- after 35 weeks was not significantly less than in mice SAMD1+/+ apoE-/- mice.

SEM of Hepatocytes and Biliary Passages in Goldfish Liver

1977 ◽  
Vol 35 ◽  
pp. 556-557
Author(s):  
Waykin Nopanitaya ◽  
Joe W. Grisham ◽  
Johnny L. Carson
Keyword(s):  
Carassius Auratus ◽  
Cell Layer ◽  
Three Dimensional ◽  
Cell Types ◽  
Biliary System ◽  
Fish Food ◽  
Commercial Fish ◽  
Goldfish Carassius Auratus ◽  
Commercial Fish Food

An interesting feature of the goldfish liver is the morphology of the hepatic plate, which is always formed by a two-cell layer of hepatocytes. Hepatic plates of the goldfish liver contain an infrequently seen second type of cell, in the centers of plates between two hepatocytes. A TEH study by Yamamoto (1) demonstrated ultrastructural differences between hepatocytes and centrally located cells in hepatic plates; the latter were classified as ductule cells of the biliary system. None of the previous studies clearly showed a three-dimensional organization of the two cell types described. In the present investigation we utilize SEM to elucidate the arrangement of hepatocytes and bile ductular cells in intralobular plates of goldfish liver.Livers from young goldfish (Carassius auratus), about 6-10 cm, fed commercial fish food were used for this study. Hepatic samples were fixed in 4% buffered paraformaldehyde, cut into pieces, fractured, osmicated, CPD, mounted Au-Pd coated, and viewed by SEM at 17-20 kV. Our observations were confined to the ultrastructure of biliary passages within intralobular plates, ductule cells, and hepatocytes.

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