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Cited by 100Nitric Oxide and Endothelin EffectsCellular Mechanics and InteractionsRedox biology and oxidative stress

MEF2B-Nox1 Signaling Is Critical for Stretch-Induced Phenotypic Modulation of Vascular Smooth Muscle Cells

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Rodríguez, Andrés I., Csányi, Gábor, Ranayhossaini, Daniel J., Feck, Douglas M., Blose, Kory J., Assatourian, Lillian, Vorp, David A., Pagano, Patrick J.·2015·Arteriosclerosis, Thrombosis, and Vascular Biology
DOI 10.1161/atvbaha.114.304936PMC PMC4409426
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Abstract

Objective—: Blood vessel hemodynamics have profound influences on function and structure of vascular cells. One of the main mechanical forces influencing vascular smooth muscle cells (VSMC) is cyclic stretch (CS). Increased CS stimulates reactive oxygen species (ROS) production in VSMC, leading to their dedifferentiation, yet the mechanisms involved are poorly understood. This study was designed to test the hypothesis that pathological CS stimulates NADPH oxidase isoform 1 (Nox1)–derived ROS via MEF2B, leading to VSMC dysfunction via a switch from a contractile to a synthetic phenotype. Approach and Results—: Using a newly developed isoform-specific Nox1 inhibitor and gene silencing technology, we demonstrate that a novel pathway, including MEF2B-Nox1-ROS, is upregulated under pathological stretch conditions, and this pathway promotes a VSMC phenotypic switch from a contractile to a synthetic phenotype. We observed that CS (10% at 1 Hz) mimicking systemic hypertension in humans increased Nox1 mRNA, protein levels, and enzymatic activity in a time-dependent manner, and this upregulation was mediated by MEF2B. Furthermore, we show that stretch-induced Nox1-derived ROS upregulated a specific marker for synthetic phenotype (osteopontin), whereas it downregulated classical markers for contractile phenotype (calponin1 and smoothelin B). In addition, our data demonstrated that stretch-induced Nox1 activation decreases actin fiber density and augments matrix metalloproteinase 9 activity, VSMC migration, and vectorial alignment. Conclusions—: These results suggest that CS initiates a signal through MEF2B that potentiates Nox1-mediated ROS production and causes VSMC to switch to a synthetic phenotype. The data also characterize a new Nox1 inhibitor as a potential therapy for treatment of vascular dysfunction in hypertension.

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  • More recent observations indicate that the ADMA/l-arginine ratios in plasma may be a better marker than either metabolite assessed independently.

    “More recent observations indicate that the ADMA/l-arginine ratios in plasma may be a better marker than either metabolite assessed independently (75, 589, 606, 790, 966).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [790]

  • Other proteins related to direct or indirect production of ROS in the cardiovascular system include peroxidases, cyclooxygenases (COX), lipoxygenases, monoamine oxidase, heme oxygenase (HO), glucose oxidase, cytochrome b5 reductase, and CYPOR.

    “Other proteins have been related to the direct or indirect production of ROS in the cardiovascular system, including, but not limited to, peroxidases, cyclooxygenases (COX), lipoxygenases, monoamine oxidase, heme oxygenase (HO), glucose oxidase, cytochrome b5 reductase, and CYPOR (209, 505, 790, 908).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [790]

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Authors
Rodríguez, A. I., Csányi, G., Ranayhossaini, D. J., Feck, D. M., Blose, K. J., Assatourian, L., Vorp, D. A., & Pagano, P. J.
Affiliations
  • From the Department of Pharmacology and Chemical Biology and Vascular Medicine Institute (A.I.R., G.C., D.J.R, D.M.F., L.A., P.J.P), and Departments of Bioengineering, Surgery, and Cardiothoracic Surgery and Center for Vascular Remodeling and Regeneration (K.J.B., D.A.V), University of Pittsburgh, PA; and Department of Basic Sciences, Faculty of Science, Universidad del Bío-Bío, Chillán, Chile (A.I.R).
  • University of Pittsburgh (US)
ORCID
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2015-02
Volume
35
Issue
2
Pages
430-438
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
DOI
10.1161/atvbaha.114.304936
PMC
PMC4409426
OpenAlex
W1996700857
Cited by
100
References
61
Citations by year
2026: 5 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 9 · 2021: 11 · 2020: 10 · 2019: 9 · 2018: 6 · 2017: 12 · 2016: 9 · 2015: 7
FWCI
6.22
Type
journal article
Language
en
Open access
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Universidade de São Paulo
  • National Heart, Lung, and Blood Institute (R01HL079207, K99HL114648, P01HL103455, R01HL112914, T32HL076124)
  • National Institute of General Medical Sciences (T32GM008424)
  • National Institute of Biomedical Imaging and Bioengineering (T32EB003392)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
MEF2B, NOX1, NADPH oxidase, reactive oxygen species, cyclic strain, vascular smooth muscle cells, phenotypic switching, osteopontin, MMP-9, VSMC migration, hypertension, vascular dysfunction
MeSH terms
NADPH Oxidase 1, Calponins, Animals, Calcium-Binding Proteins, Cell Movement, Cells, Cultured, Cytoskeletal Proteins, Enzyme Inhibitors, Microfilament Proteins, Muscle Proteins, Muscle, Smooth, Vascular, NADH, NADPH Oxidoreductases, Phenotype, Pressoreceptors, RNA, Messenger, Time Factors, Transfection, Biomarkers, Reactive Oxygen Species, Matrix Metalloproteinase 9, Myocytes, Smooth Muscle, RNA Interference, Mechanotransduction, Cellular, Rats, Osteopontin, MEF2 Transcription Factors, Vascular Remodeling

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