scholarly journals SAMD1 Distribution Patterns in Mouse Atherosclerosis Models Suggest Roles in LDL Retention, Antigen Presentation, and Cell Phenotype Modulation

2021 ◽  
Author(s):  
Bruce Campbell ◽  
Patricia Bourassa ◽  
Robert Aiello
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Foam Cell ◽  
Ex Vivo ◽  
Muscle Cells ◽  
Distribution Patterns ◽  
Lesion Size ◽  
Cell Phenotype ◽  
Lesion Growth

The theory that lesions formed by retention of circulating LDL can then progress to complicated atherosclerotic lesions has been a subject of debate, as has the mechanism of retention. In earlier work, we identified SAMD1, a protein expressed by intimal smooth muscle cells in human lesions that appears to irreversibly bind apoB-Lps in extracellular matrix near the lumen. We hypothesized this binding could contribute to the formation of lesions in mice, and that inhibiting binding could reduce lesion growth. In mouse models of atherosclerosis, we found that SAMD1 binds LDL; that SAMD1/apoB complex is ingested by intimal cells; and that recognizable epitopes of the SAMD1/apoB complex survive some degree of catabolism in foam cell. These data appear to support the SAMD1/LDL retention hypothesis of lesion growth. Despite apparently irreversible binding of human LDL to full-length human SAMD1, efficient anti-SAMD1-antibody inhibitors were created. In vivo lesion targeting of inhibitors was demonstrated by MRI, ultrasound, and ex vivo microscopy. However, only non-statistically significant reductions in spontaneous lesion size in apoE-/- mice were seen after 12 weeks of treatment with PEG-fab inhibitors of SAMD1/LDL binding. In contrast, inhibitors substantially reduced LDL retention in carotid injury lesions in apoE-/- and LDLR-/- mice 7 days after injury. The most obvious difference between injury lesions and early spontaneous lesions is the presence of numerous SMCs and associated ECM in the injury lesions. Thus, SAMD1 may be involved in retention of apoB-Lps in mouse lesions, but not until smooth muscle cells have entered the intima. In addition, SAMD1 is seen throughout arteries in changing patterns that suggest broader and more complicated roles in atherosclerosis.

scholarly journals Cooperative action of APJ and α1A-adrenergic receptor in vascular smooth muscle cells induces vasoconstriction

2019 ◽  
Vol 166 (5) ◽  
pp. 383-392 ◽  
Author(s):  
Katsumasa Nagano ◽  
Chulwon Kwon ◽  
Junji Ishida ◽  
Tatsuo Hashimoto ◽  
Jun-Dal Kim ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Adrenergic Receptor ◽  
Calcium Influx ◽  
Ex Vivo ◽  
Smooth Muscle Actin ◽  
Muscle Cells ◽  
Cooperative Action ◽  
A Genome

Abstract The apelin receptor (APJ), a receptor for apelin and elabela/apela, induces vasodilation and vasoconstriction in blood vessels. However, the prolonged effects of increased APJ-mediated signalling, involving vasoconstriction, in smooth muscle cells have not been fully characterized. Here, we investigated the vasoactive effects of APJ gain of function under the control of the smooth muscle actin (SMA) gene promoter in mice. Transgenic overexpression of APJ (SMA-APJ) conferred sensitivity to blood pressure and vascular contraction induced by apelin administration in vivo. Interestingly, ex vivo experiments showed that apelin markedly increased the vasoconstriction of isolated aorta induced by noradrenaline (NA), an agonist for α- and β-adrenergic receptors, or phenylephrine, a specific agonist for α1-adrenergic receptor (α1-AR). In addition, intracellular calcium influx was augmented by apelin with NA in HEK293T cells expressing APJ and α1A-AR. To examine the cooperative action of APJ and α1A-AR in the regulation of vasoconstriction, we developed α1A-AR deficient mice using a genome-editing technique, and then established SMA-APJ/α1A-AR-KO mice. In the latter mouse line, aortic vasoconstriction induced by a specific agonist for α1A-AR, A-61603, were significantly less than in SMA-APJ mice. These results suggest that the APJ-enhanced response requires α1A-AR to contract vessels coordinately.

scholarly journals TRPML1 channels initiate Ca2+ sparks in vascular smooth muscle cells

2020 ◽  
Vol 13 (637) ◽  
pp. eaba1015 ◽  
Author(s):  
Pratish Thakore ◽  
Harry A. T. Pritchard ◽  
Caoimhin S. Griffin ◽  
Evan Yamasaki ◽  
Bernard T. Drumm ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Transient Receptor Potential ◽  
Ex Vivo ◽  
Ryanodine Receptors ◽  
Muscle Cells ◽  
Confocal Imaging

TRPML1 (transient receptor potential mucolipin 1) is a Ca2+-permeable, nonselective cation channel localized to the membranes of endosomes and lysosomes and is not present or functional on the plasma membrane. Ca2+ released from endosomes and lysosomes into the cytosol through TRPML1 channels is vital for trafficking, acidification, and other basic functions of these organelles. Here, we investigated the function of TRPML1 channels in fully differentiated contractile vascular smooth muscle cells (SMCs). In live-cell confocal imaging studies, we found that most endosomes and lysosomes in freshly isolated SMCs from cerebral arteries were essentially immobile. Using nanoscale super-resolution microscopy, we found that TRPML1 channels present in late endosomes and lysosomes formed stable complexes with type 2 ryanodine receptors (RyR2) on the sarcoplasmic reticulum (SR). Spontaneous Ca2+ signals resulting from the release of SR Ca2+ through RyR2s (“Ca2+ sparks”) and corresponding Ca2+-activated K+ channel activity are critically important for balancing vasoconstriction. We found that these signals were essentially absent in SMCs from TRPML1-knockout (Mcoln1−/−) mice. Using ex vivo pressure myography, we found that loss of this critical signaling cascade exaggerated the vasoconstrictor responses of cerebral and mesenteric resistance arteries. In vivo radiotelemetry studies showed that Mcoln1−/− mice were spontaneously hypertensive. We conclude that TRPML1 is crucial for the initiation of Ca2+ sparks in SMCs and the regulation of vascular contractility and blood pressure.

scholarly journals Combination of histochemical analyses and micro-MRI reveals regional changes of the murine cervix in preparation for labor

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Antara Chatterjee ◽  
Rojan Saghian ◽  
Anna Dorogin ◽  
Lindsay S. Cahill ◽  
John G. Sled ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Diffusion Tensor ◽  
Ex Vivo ◽  
Muscle Cells ◽  
Pregnant Mouse ◽  
Collagen Fibers ◽  
Muscular Layer ◽  
Tissue Organization ◽  
Picrosirius Red

AbstractThe cervix is responsible for maintaining pregnancy, and its timely remodeling is essential for the proper delivery of a baby. Cervical insufficiency, or “weakness”, may lead to preterm birth, which causes infant morbidities and mortalities worldwide. We used a mouse model of pregnancy and term labor, to examine the cervical structure by histology (Masson Trichome and Picrosirius Red staining), immunohistochemistry (Hyaluronic Acid Binding Protein/HABP), and ex-vivo MRI (T2-weighted and diffusion tensor imaging), focusing on two regions of the cervix (i.e., endocervix and ectocervix). Our results show that mouse endocervix has a higher proportion of smooth muscle cells and collagen fibers per area, with more compact tissue structure, than the ectocervix. With advanced gestation, endocervical changes, indicative of impending delivery, are manifested in fewer smooth muscle cells, expansion of the extracellular space, and lower presence of collagen fibers. MRI detected three distinctive zones in pregnant mouse endocervix: (1) inner collagenous layer, (2) middle circular muscular layer, and (3) outer longitudinal muscular layer. Diffusion MRI images detected changes in tissue organization as gestation progressed suggesting the potential application of this technique to non-invasively monitor cervical changes that precede the onset of labor in women at risk for preterm delivery.

scholarly journals Stromal cells from human long-term marrow cultures are mesenchymal cells that differentiate following a vascular smooth muscle differentiation pathway

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 66-76 ◽  
Author(s):  
MC Galmiche ◽  
VE Koteliansky ◽  
J Briere ◽  
P Herve ◽  
P Charbord
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Stromal Cells ◽  
Muscle Cells ◽  
Mesenchymal Cells ◽  
Myoid Cells ◽  
Marrow Cultures

In human long-term marrow cultures connective tissue-forming stromal cells are an essential cellular component of the adherent layer where granulomonocytic progenitors are generated from week 2 onward. We have previously found that most stromal cells in confluent cultures were stained by monoclonal antibodies directed against smooth muscle- specific actin isoforms. The present study was carried out to evaluate the time course of alpha-SM-positive stromal cells and to search for other cytoskeletal proteins specific for smooth muscle cells. It was found that the expression of alpha-SM in stromal cells was time dependent. Most of the adherent spindle-shaped, vimentin-positive stromal cells observed during the first 2 weeks of culture were alpha- SM negative. On the contrary, from week 3 to week 7, most interdigitated stromal cells contained stress fibers whose backbone was made of alpha-SM-positive microfilaments. In addition, in confluent cultures, other proteins specific for smooth muscle were detected: metavinculin, h-caldesmon, smooth muscle myosin heavy chains, and calponin. This study confirms the similarity between stromal cells and smooth muscle cells. Moreover, our results reveal that cells in vivo with the phenotype closest to that of stromal cells are immature fetal smooth muscle cells and subendothelial intimal smooth muscle cells; a cell subset with limited development following birth but extensively recruited in atherosclerotic lesions. Stromal cells very probably derive from mesenchymal cells that differentiate along this distinctive vascular smooth muscle cell pathway. In humans, this differentiation seems crucial for the maintenance of granulomonopoiesis. These in vitro studies were completed by examination of trephine bone marrow biopsies from adults without hematologic abnormalities. These studies revealed the presence of alpha-SM-positive cells at diverse locations: vascular smooth muscle cells in the media of arteries and arterioles, pericytes lining capillaries, myoid cells lining sinuses at the abluminal side of endothelial cells or found within the hematopoietic logettes, and endosteal cells lining bone trabeculae. More or less mature cells of the granulocytic series were in intimate contact with the thin cytoplasmic extensions of myoid cells. Myoid cells may be the in vivo counterpart of stromal cells with the above-described vascular smooth muscle phenotype.

scholarly journals Inflammatory process in atherogenesis: New facts about old flame

2012 ◽  
Vol 65 (9-10) ◽  
pp. 388-395 ◽  
Author(s):  
Danijela Vucevic ◽  
Djordje Radak ◽  
Tatjana Radosavljevic ◽  
Dusan Mladenovic ◽  
Ivan Milovanovic
Keyword(s):  
Smooth Muscle ◽  
Endothelial Dysfunction ◽  
Smooth Muscle Cells ◽  
Inflammatory Process ◽  
Foam Cell ◽  
Muscle Cells ◽  
Low Density Lipoproteins ◽  
Foam Cell Formation ◽  
Low Density ◽  
Mediators Of Inflammation

Introduction. Atherosclerosis is a progressive, multifactorial, diffuse, multisystemic, chronic, inflammatory disease, which is manifested by disorders of vascular, immune and metabolic system. Pathogenesis of this disease is not fully understood. Endothelial Dysfunction and Inflammatory Process. Endothelial dysfunction is recognized as the crucial step in atherogenesis. A lot of studies have confirmed the involvement of various mediators of inflammation in initial proatherogenic processes, such as the upregulation of adhesion molecules on endothelial cells, binding of low density lipoproteins to endothelium, activation of macrophages and proliferation of vascular smooth muscle cells. Fatty stain and Inflammatory Process. Fatty stain consists of foam cell accumulation. After foam cell formation, mediators of inflammation initiate a series of intracellular events that include the induction of inflammatory cytokines. Thus, a vicious circle of inflammation, modification of lipoproteins and further inflammation can be maintained in the artery. Transitory Lesion and Inflammatory Process. In transitory lesion intensive phagocytosis of oxidized low density lipoproteins additionally activates monocytes and macrophages and consequently facilitates and exacerbates the inflammatory response. Fibrotic Plaque and Inflammatory Process. Inflammatory process, matrix-degrading metalloproteinases activity, platelets aggregation and smooth muscle cells proliferation play a central role in development of fibrotic plaque. Complex Lesion and Inflammatory Process. It has been shown that inflammation is closely related to the development of atherosclerotic plaque rupture. Conclusion. The contribution of inflammatory process has become increasingly meaningful in understanding the initiation, progression and clinical manifestations of atherosclerosis.

scholarly journals Induction of cyclooxygenase-2 in rat vascular smooth muscle cells in vitro and in vivo.

1994 ◽  
Vol 269 (11) ◽  
pp. 8504-8509
Author(s):  
K.A. Pritchard ◽  
M.K. O'Banion ◽  
J.M. Miano ◽  
N. Vlasic ◽  
U.G. Bhatia ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Cyclooxygenase 2
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