scholarly journals Nanoparticle-mediated microRNA-145 Delivery for Vascular Smooth Muscle Cell Phenotype Modulation and Atherosclerosis Treatment

2020 ◽  
Author(s):  
Deborah D. Chin ◽  
Christopher Poon ◽  
Jonathan Wang ◽  
Johan Joo ◽  
Victor Ong ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Targeted Delivery ◽  
Early Stage ◽  
Phenotypic Switching ◽  
Cell Phenotype ◽  
Lesion Growth ◽  
Binding Peptides ◽  
Atherosclerosis Treatment

AbstractVascular smooth muscle cells (VSMCs) change from contractile to the synthetic phenotype during atherogenesis and 30-70% of cells that make up plaques have been elucidated to be of VSMC origin. MicroRNA-145 (miR-145) is responsible for regulating VSMC phenotypic switching, and low miR-145 levels in circulation have been linked with atherosclerosis. Hence, we developed nanoparticles for targeted delivery of miR-145 by synthesizing micelles co-assembled with miR-145 and the CCR2-binding peptides for plaque targeting. The miR cargo was protected in micelles from premature endosomal degradation and rescued contractile markers in synthetic VSMCs and SMCs isolated from patient arteries in vitro. In ApoE-/- mid-stage atherosclerotic mice, miR-145 micelles halted plaque growth and maintained contractile phenotypes similar to baseline levels. In early-stage atherosclerosis, a single dose of miR-145 micelles prevented lesion growth by 49%. We present the potential of miR-145 micelles as a therapeutic that can be applied longitudinally and intervene throughout atherosclerosis pathogenesis.

scholarly journals Matrix stiffness and blood pressure together regulate vascular smooth muscle cell phenotype switching and cofilin dependent podosome formation

2020 ◽  
Author(s):  
Brian Sit ◽  
Zhen Feng ◽  
Ioannis Xanthis ◽  
Emilie Marhuenda ◽  
Simona Zingaro ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Phenotypic Switching ◽  
Cell Phenotype ◽  
Matrix Stiffness ◽  
Cellular Mechanics ◽  
Soft Matrix ◽  
Phenotype Switch ◽  
The Impact ◽  
Progression Of Atherosclerosis

AbstractVascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. In pre-atherosclerotic lesions, VSMCs switch from a contractile to a synthetic phenotype and subsequently remodel the microenvironment, leading to further disease progression. Ageing and associated mechanical changes of the extracellular matrix as well as hypertension are major risk of atherosclerosis. Consequently, we sought here to systematically study the impact of mechanical and chemical stimulations on VSMC phenotypic switching. We find that the hemodynamic pressure and matrix stiffness have overlapping effects and together contribute to the phenotypic changes in cellular mechanics, podosome formation, and matrix degradation. We further identify cofilin as a key modulator of the mechanosensitive phenotype switch, which is regulated through Ca2+/slingshot-dependent pressure sensing and RhoA/ROCK-dependent stiffness sensing pathways. Altogether, microenvironment stimulations of high pressure and soft matrix collectively promote the cofilin activity, VSMC migration, and the early progression of atherosclerosis.

The effects of stretch on vascular smooth muscle cell phenotype in vitro

2008 ◽  
Vol 17 (2) ◽  
pp. 98-102 ◽  
Author(s):  
Anastassi T. Halka ◽  
Neill J. Turner ◽  
Andrew Carter ◽  
Jonathan Ghosh ◽  
Michael O. Murphy ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Cell Phenotype ◽  
Smooth Muscle Cell Phenotype

scholarly journals Oxidized Phospholipids Induce Phenotypic Switching of Vascular Smooth Muscle Cells In Vivo and In Vitro

2007 ◽  
Vol 101 (8) ◽  
pp. 792-801 ◽  
Author(s):  
Nataliya A. Pidkovka ◽  
Olga A. Cherepanova ◽  
Tadashi Yoshida ◽  
Matthew R. Alexander ◽  
Rebecca A. Deaton ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Phenotypic Switching ◽  
Oxidized Phospholipids

scholarly journals Vitamin D Promotes Trophoblast Cell Induced Separation of Vascular Smooth Muscle Cells in Vascular Remodeling via Induction of G-CSF

2020 ◽  
Vol 8 ◽  
Author(s):  
Joy Yue Zhang ◽  
Peihuang Wu ◽  
Danyang Chen ◽  
Fen Ning ◽  
Qinsheng Lu ◽  
...  
Keyword(s):  
Vitamin D ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Remodeling ◽  
Ex Vivo ◽  
Extravillous Trophoblast ◽  
Phenotypic Switching ◽  
Obstetric Outcomes ◽  
Chorionic Plate

Vitamin D deficiency is associated with complications of pregnancy such as pre-eclampsia, fetal growth restriction, and miscarriage, all of which are also associated with incomplete spiral artery (SpA) remodeling. We have previously shown that both uterine natural killer (uNK) cells and extravillous trophoblast cells (EVT) are required for successful SpA remodeling, but whether their activity in this process is modulated by vitamin D is not known. In the current study, we use a previously described chorionic plate artery (CPA) ex vivo model of vascular remodeling to determine the effects of 1,25(OH)2D treated uNK cell, placental explant (PEx), and uNK/PEx conditioned medium (CM) on vascular smooth muscle cell (VSMC) disorganization and phenotypic switching. Significant results were followed up in VSMCs in vitro. We demonstrate that 1,25(OH)2D can enhance the ability of PEx to induce SpA remodeling, via a mechanism associated with increased secretion of granulocyte-colony stimulating factor (G-CSF). G-CSF appears able to increase VSMC disorganization and phenotypic switching in both an ex vivo vascular model and in vitro VSMC cultures. The clinical relevance of these findings are still to be determined. G-CSF may have differential effects depending on dose and vascular bed, and vitamin D may play a role in potentiating these actions. G-CSF may be an interesting potential therapeutic target for facilitating physiological vascular remodeling for the prevention of adverse obstetric outcomes.

scholarly journals Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wei-Wen Lim ◽  
Ben Corden ◽  
Benjamin Ng ◽  
Konstantinos Vanezis ◽  
Giuseppe D’Agostino ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Vascular Inflammation ◽  
Arterial Disease ◽  
Phenotypic Switching ◽  
Autocrine Loop ◽  
Interleukin 11

Abstract Transforming growth factor beta-1 (TGFβ1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease. We performed RNA-sequencing of TGFβ1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFβ1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFβ1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.

Plasticity-related gene-1 inhibits lysophosphatidic acid-induced vascular smooth muscle cell migration and proliferation and prevents neointima formation

2012 ◽  
Vol 303 (10) ◽  
pp. C1104-C1114 ◽  
Author(s):  
Amira Gaaya ◽  
Odette Poirier ◽  
Nathalie Mougenot ◽  
Tiphaine Hery ◽  
Fabrice Atassi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Lysophosphatidic Acid ◽  
Cell Phenotype ◽  
Related Gene ◽  
Neointimal Formation ◽  
Vsmc Proliferation

Plasticity-related gene-1 (PRG-1) protects neuronal cells from lysophosphatidic acid (LPA) effects. In vascular smooth muscle cells (VSMCs), LPA was shown to induce phenotypic modulation in vitro and vascular remodeling in vivo. Thus we explored the role of PRG-1 in modulating VSMC response to LPA. PCR, Western blot, and immunofluorescence experiments showed that PRG-1 is expressed in rat and human vascular media. PRG-1 expression was strongly inhibited in proliferating compared with quiescent VSMCs both in vitro and in vivo (medial vs. neointimal VSMCs), suggesting that PRG-1 expression is dependent on the cell phenotype. In vitro, adenovirus-mediated overexpression of PRG-1 specifically inhibited LPA-induced rat VSMC proliferation and migration but not platelet-derived growth factor-induced proliferation. This effect was abolished by mutation of a conserved histidine in the lipid phosphate phosphatase family that is essential for interaction with lipid phosphates. In vivo, balloon-induced neointimal formation in rat carotid was significantly decreased in vessels infected with PRG-1 adenovirus compared with β-galactosidase adenovirus (−71%; P < 0.05). PRG-1 overexpression abolished the activation of the p42/p44 signaling pathway in LPA-stimulated rat VSMCs in culture and in balloon-injured rat carotids. Taken together, these findings provide the first evidence of a protective role of PRG-1 in the vascular media under pathophysiological conditions.

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