scholarly journals Neointimal remodeling in carotid atherosclerosis: roles of matrix metalloproteinases-2 and -9 and different phenotypes of vascular smooth muscle cells

2020 ◽  
pp. 20-30
Author(s):  
Л.А. Богданов ◽  
Е.А. Великанова ◽  
Д.К. Шишкова ◽  
А.Р. Шабаев ◽  
А.Г. Кутихин
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Smooth Muscle Actin ◽  
Muscle Cells ◽  
Atherosclerotic Plaques ◽  
Double Positive ◽  
Fibrous Cap ◽  
The Media

Цель исследования - изучение распространенности и локализации сосудистых гладкомышечных клеток (СГМК) различного фенотипа в составе атеросклеротических бляшек сонной артерии, а также взаимосвязи различных клеточных популяций неоинтимы с экспрессией матриксных металлопротеиназ (ММП)-2 и ММП-9 в зависимости от степени стабильности бляшки. Методы. Проведено иммуногистохимическое исследование 16 атеросклеротических бляшек (8 клинически нестабильных и 8 стабильных), полученных при каротидной эндартерэктом в связи с гемодинамически значимым стенозом. Оценка сократительной способности СГМК проводилась при использовании метода иммуногистохимического типирования альфа-актина гладких мышц (α-SMA), синтетического, макрофагального и остеогенного фенотипов СГМК посредством типирования виметина, СВ68 и RUNX2 соответственно. Активность ремоделирования определялась посредством выявления ММП-2 и ММП-9. Результаты. Показано, что около трети каротидных бляшек характеризовались высокой экспрессией MMП-9 CD68-положительными клетками, что не коррелировало с их нестабильностью. Локализация, содержание и соотношение СГМК различного фенотипа и макрофагов значительно варьировали в зависимости от бляшки. Общей закономерностью было преимущественное послойное типирование на α-SMA в зоне интактных эластических волокон медии и, реже, в фиброзной покрышке или прилегающих участках. CD68-положительные клетки визуализировались в толще неоинтимы; некоторая их доля была колокализована с α-SMA, отражая СГМК макрофагального фенотипа. Положительное реакция на виментин наблюдалась на границе с эластическими волокнами медии, либо с основной клеточной массой неоинтимы и характеризовалась прилегающим бесклеточным экстрацеллюлярным матриксом, что свидетельствовало об активном синтезе его соответствующими клетками. Также в неоинтиме обнаруживались клетки положительные как на RUNX2 и α-SMA, так и исключительно RUNX2-положительные клетки. Заключение. Каротидные атеросклеротические бляшки характеризуются различной локализацией, содержанием и соотношением СГМК сократительного, синтетического, макрофагального и остеогенного фенотипов, при этом экспрессия ММП-2 и ММП-9 была ограничена CD68-положительными макрофагами и СГМК макрофагального фенотипа. Aim.To study prevalence and localization of different phenotypes of vascular smooth muscle cells (VSMCs) in carotid atherosclerotic plaques and to examine expression of matrix metalloproteinase (MMP)-2 and MMP-9 in relation to different cell populations within the neointima. Methods. The immunohistochemical examination was performed on 16 atherosclerotic plaques (8 unstable and 8 stable) excised during carotid endarterectomy for critical stenosis. VSMCs of contractile, synthetic, macrophagic, and osteogenic phenotypes were identified by staining for α-smooth muscle actin (α-SMA), vimentin, CD68, and RUNX2, respectively. Activity of neointimal remodeling was assessed by staining for MMP-2 and MMP-9. Results. Approximately one-third of atherosclerotic plaques was positively stained for MMP-9 exclusively expressed in CD68-positive cells, which however, did not correlate with plaque ruptures. Localization, content, and ratio of different VSCM phenotypes significantly varied in different plaques. Positive α-SMA staining was found mainly in the intact media and fibrous cap. In contrast, both CD68-positive and CD68/α-SMA double-positive cells were detected within the neointima but not in the media. Vimentin was expressed in the neointima between the medial layers and fibrous cap near the acellular extracellular matrix suggesting its active production by mesenchymal cells. Both RUNX2- and RUNX2 α-SMA double-positive cells indicative of VSMC osteogenic differentiation were also observed in the neointima. Conclusion. Carotid atherosclerotic plaques contained VSMCs of all phenotypes, which were differentially localized within the neointima; however, the MMP-2 and MMP-9 expression was restricted to CD68-positive macrophages and CD68/α-SMA-positive VSMCs of the macrophagal phenotype.

scholarly journals Vascular smooth muscle cells in atherosclerosis: time for a re-assessment

2021 ◽  
Author(s):  
Mandy O J Grootaert ◽  
Martin R Bennett
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Atherosclerotic Lesion ◽  
Muscle Cells ◽  
Lineage Tracing ◽  
Phenotypic Switching ◽  
Fibrous Cap ◽  
The Media

Abstract Vascular smooth muscle cells (VSMCs) are key participants in both early and late-stage atherosclerosis. VSMCs invade the early atherosclerotic lesion from the media, expanding lesions, but also forming a protective fibrous cap rich in extracellular matrix to cover the ‘necrotic’ core. Hence, VSMCs have been viewed as plaque-stabilizing, and decreased VSMC plaque content—often measured by expression of contractile markers—associated with increased plaque vulnerability. However, the emergence of lineage-tracing and transcriptomic studies has demonstrated that VSMCs comprise a much larger proportion of atherosclerotic plaques than originally thought, demonstrate multiple different phenotypes in vivo, and have roles that might be detrimental. VSMCs down-regulate contractile markers during atherosclerosis whilst adopting alternative phenotypes, including macrophage-like, foam cell-like, osteochondrogenic-like, myofibroblast-like, and mesenchymal stem cell-like. VSMC phenotypic switching can be studied in tissue culture, but also now in the media, fibrous cap and deep-core region, and markedly affects plaque formation and markers of stability. In this review, we describe the different VSMC plaque phenotypes and their presumed cellular and paracrine functions, the regulatory mechanisms that control VSMC plasticity, and their impact on atherogenesis and plaque stability.

scholarly journals Maintenance of AMPK activation by metformin is beneficial for suppressing the progress of diabetes-accelerated atherosclerosis via inhibition of vascular smooth muscle cells migration

2020 ◽  
Author(s):  
Yi Yan ◽  
Ting Li ◽  
Zhonghao Li ◽  
Mingyuan He ◽  
Dejiang Wang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
High Fat Diet ◽  
Muscle Cells ◽  
Atherosclerotic Plaques ◽  
Ampk Activation ◽  
High Fat ◽  
Accelerated Atherosclerosis

Abstract Background: Our previous work revealed that augmented AMPK activation inhibit cell migration by phosphorylating its substrate Pdlim5. As medial VSMCs contribute to the major composition of atherosclerotic plaques, a hypothesis is raised that modulation of AMPK-Pdlim5 signal pathway could retard the development of atherosclerosis through inhibiting migration of VSMCs. Therefore, we initiate the present study to investigate whether AMPK agonist like metformin is beneficial for suppressing diabetes-accelerated atherosclerosis in a diabetic mouse model induced by streptozotocin and high fat diet.Methods: For cell experiment, vascular smooth muscle cells (VSMCs) were overexpressed flag fused Pdlim5 and Pdlim5 mutant. Then the engineered VSMCs were introduced with metformin or control drug before determination of phosphorylated Pdlim5 with immunoblotting. For animal work, 8-week-old male ApoE−/−mice were induced diabetes with streptozotocin and then were randomly divided into 8 groups: control group, metformin hydrochloride (300 mg/kg/day) group, wildtype-Pdlim5 (Pdlim5 WT) carried adenovirus (Ad) group, Ad Pdlim5 WT and Met group, Ad Pdlim5 S177A group, Ad Pdlim5 S177A and Met group, Ad Pdlim5 S177D group, Ad Pdlim5 S177D and Met group. All mice were fed with high fat diet after virus infection. At the end, mice were sacrificed to observe atherosclerotic plaques and deposition of VSMCs in plaques. Moreover, 12–15-week-old Myh11-cre-EGFP male mice were accepted ligation of the left carotid artery and randomly divided into control and metformin treatment group. Finally, the injured vessel of Myh11-cre-EGFP mice were isolated to analyze the relationship between AMPK activation and neointima formation.Results: It was found that AMPK directly phosphorylate Pdlim5 at Ser177 in vitro, and metformin, an AMPK agonist, could induce phosphorylation of Pdlim5 indirectly and inhibition of cell migration as a result. Exogenous expression of phosphomimetic S177D-Pdlim5 inhibits lamellipodia formation and migration in VSMCs. It was also demonstrated that VSMCs contribute to the major composition of injury-induced neointimal lesions, while metformin could alleviate the occlusion of carotid artery in a wire-injury mice model. In order to investigate the function of AMPK-Pdlim5 pathway in the context of pathological condition, ApoE−/− male mice were divided randomly into control, streptozocin and high fat diet-induced diabetes mellitus, STZ + HFD together with metformin or Pdlim5 mutant carried adenovirus treatment groups. The results showed increased plasma lipids and aggravated vascular smooth muscle cells infiltration into the atherosclerotic lesion in diabetic mice compared with control mice. However, metformin alleviated diabetes-induced metabolic disorders and atherosclerosis, as well as decreased VSMCs infiltration in atherosclerotic plaques, while Pdlim5 phospho-abolished mutant carried adenovirus S177A-Pdlim5 undermine this protective function.Conclusions: The activation of AMPK-Pdlim5 pathway by chemicals like Metformin could inhibit formation of migratory machine of VSMCs and alleviate the progress of atherosclerotic plaques in diabetic mice. The maintenance of AMPK activity is beneficial for suppressing diabetes-accelerated atherosclerosis or metabolic syndrome.

scholarly journals S100B is required for maintaining an intermediate state with double-positive Sca-1+ progenitor and vascular smooth muscle cells during neointimal formation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yan Wu ◽  
Xin Liu ◽  
Ling-Yun Guo ◽  
Lei Zhang ◽  
Fei Zheng ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Progenitor Cells ◽  
Vascular Smooth Muscle Cells ◽  
Intermediate State ◽  
Muscle Cells ◽  
Neointimal Formation ◽  
Double Positive ◽  
Vessel Injury

Abstract Introduction Accumulation of vascular smooth muscle cells (VSMCs) within the neointimal region is a hallmark of atherosclerosis and vessel injury. Evidence has shown that Sca-1-positive (Sca-1+) progenitor cells residing in the vascular adventitia play a crucial role in VSMC assemblages and intimal lesions. However, the underlying mechanisms, especially in the circumstances of vascular injury, remain unknown. Methods and results The neointimal formation model in rats was established by carotid artery balloon injury using a 2F-Forgaty catheter. Most Sca-1+ cells first appeared at the adventitia of the vascular wall. S100B expressions were highest within the adventitia on the first day after vessel injury. Along with the sequentially increasing trend of S100B expression in the intima, media, and adventitia, respectively, the numbers of Sca-1+ cells were prominently increased at the media or neointima during the time course of neointimal formation. Furthermore, the Sca-1+ cells were markedly increased in the tunica media on the third day of vessel injury, SDF-1α expressions were obviously increased, and SDF-1α levels and Sca-1+ cells were almost synchronously increased within the neointima on the seventh day of vessel injury. These effects could effectually be reversed by knockdown of S100B by shRNA, RAGE inhibitor (SPF-ZM1), or CXCR4 blocker (AMD3100), indicating that migration of Sca-1+ cells from the adventitia into the neointima was associated with S100B/RAGE and SDF-1α/CXCR4. More importantly, the intermediate state of double-positive Sca-1+ and α-SMA cells was first found in the neointima of injured arteries, which could be substantially abrogated by using shRNA for S100B or blockade of CXCR4. S100B dose-dependently regulated SDF-1α expressions in VSMCs by activating PI3K/AKT and NF-κB, which were markedly abolished by PI3K/AKT inhibitor wortmannin and enhanced by p65 blocker PDTC. Furthermore, S100B was involved in human umbilical cord-derived Sca-1+ progenitor cells’ differentiation into VSMCs, especially in maintaining the intermediate state of double-positive Sca-1+ and α-SMA. Conclusions S100B triggered neointimal formation in rat injured arteries by maintaining the intermediate state of double-positive Sca-1+ progenitor and VSMCs, which were associated with direct activation of RAGE by S100B and indirect induction of SDF-1α by activating PI3K/AKT and NF-κB.

Expression and function of periostin-like factor in vascular smooth muscle cells

2007 ◽  
Vol 292 (5) ◽  
pp. C1672-C1680 ◽  
Author(s):  
Judith Litvin ◽  
Xing Chen ◽  
Sheri Keleman ◽  
Shimei Zhu ◽  
Michael Autieri
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Clinical Manifestations ◽  
Muscle Cells ◽  
Antibody Treatment ◽  
The Media ◽  
Vascular Proliferative Diseases ◽  
And Function

In injured blood vessels activated vascular smooth muscle cells (VSMCs) migrate from the media to the intima, proliferate and synthesize matrix proteins. This results in occlusion of the lumen and detrimental clinical manifestations. We have identified a novel isoform of the periostin family of proteins referred to as periostin-like factor (PLF). PLF expression in VSMCs was increased following treatment with mitogenic compounds, suggesting that PLF plays a role in VSMC activation. Correspondingly, proliferation of the cells was significantly reduced with anti-PLF antibody treatment. PLF expression increased VSMC migration, an essential cellular process leading to vascular restenosis after injury. PLF protein was localized to neointimal VSMC of rat and swine balloon angioplasty injured arteries, as well as in human arteries with transplant restenosis, supporting the hypothesis that PLF is involved in VSMC activation and vascular proliferative diseases. Taken together, these data suggest a role for PLF in the regulation of vascular proliferative disease.

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