Tissue Transglutaminase Modulates Vascular Stiffness and Function Through Crosslinking‐Dependent and Crosslinking‐Independent Functions

Jochen Steppan; Yehudit Bergman; Kayla Viegas; Dinani Armstrong; Siqi Tan; Huilei Wang; Sean Melucci; Daijiro Hori; Sung Yong Park; Sebastian F. Barreto; Abraham Isak; Sandeep Jandu; Nicholas Flavahan; Mark Butlin; Steven S. An; Alberto Avolio; Dan E. Berkowitz; Marc K. Halushka; Lakshmi Santhanam

doi:10.1161/JAHA.116.004161

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease (Feb 2017)

Tissue Transglutaminase Modulates Vascular Stiffness and Function Through Crosslinking‐Dependent and Crosslinking‐Independent Functions

Jochen Steppan,
Yehudit Bergman,
Kayla Viegas,
Dinani Armstrong,
Siqi Tan,
Huilei Wang,
Sean Melucci,
Daijiro Hori,
Sung Yong Park,
Sebastian F. Barreto,
Abraham Isak,
Sandeep Jandu,
Nicholas Flavahan,
Mark Butlin,
Steven S. An,
Alberto Avolio,
Dan E. Berkowitz,
Marc K. Halushka,
Lakshmi Santhanam

Affiliations

Jochen Steppan: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University, Baltimore, MD
Yehudit Bergman: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University, Baltimore, MD
Kayla Viegas: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
Dinani Armstrong: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University, Baltimore, MD
Siqi Tan: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD
Huilei Wang: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD
Sean Melucci: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD
Daijiro Hori: Department of Surgery, Johns Hopkins University, Baltimore, MD
Sung Yong Park: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University, Baltimore, MD
Sebastian F. Barreto: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University, Baltimore, MD
Abraham Isak: Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, MD
Sandeep Jandu: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University, Baltimore, MD
Nicholas Flavahan: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University, Baltimore, MD
Mark Butlin: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
Steven S. An: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD
Alberto Avolio: Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia
Dan E. Berkowitz: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University, Baltimore, MD
Marc K. Halushka: Department of Pathology, Johns Hopkins University, Baltimore, MD
Lakshmi Santhanam: Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University, Baltimore, MD

DOI: https://doi.org/10.1161/JAHA.116.004161
Journal volume & issue: Vol. 6, no. 2

Abstract

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BackgroundThe structural elements of the vascular wall, namely, extracellular matrix and smooth muscle cells (SMCs), contribute to the overall stiffness of the vessel. In this study, we examined the crosslinking‐dependent and crosslinking‐independent roles of tissue transglutaminase (TG2) in vascular function and stiffness. Methods and ResultsSMCs were isolated from the aortae of TG2−/− and wild‐type (WT) mice. Cell adhesion was examined by using electrical cell–substrate impedance sensing and PicoGreen assay. Cell motility was examined using a Boyden chamber assay. Cell proliferation was examined by electrical cell–substrate impedance sensing and EdU incorporation assays. Cell micromechanics were studied using magnetic torsion cytometry and spontaneous nanobead tracer motions. Aortic mechanics were examined by tensile testing. Vasoreactivity was studied by wire myography. SMCs from TG2−/− mice had delayed adhesion, reduced motility, and accelerated de‐adhesion and proliferation rates compared with those from WT. TG2−/− SMCs were stiffer and displayed fewer cytoskeletal remodeling events than WT. Collagen assembly was delayed in TG2−/− SMCs and recovered with adenoviral transduction of TG2. Aortic rings from TG2−/− mice were less stiff than those from WT; stiffness was partly recovered by incubation with guinea pig liver TG2 independent of crosslinking function. TG2−/− rings showed augmented response to phenylephrine‐mediated vasoconstriction when compared with WT. In human coronary arteries, vascular media and plaque, high abundance of fibronectin expression, and colocalization with TG2 were observed. ConclusionsTG2 modulates vascular function/tone by altering SMC contractility independent of its crosslinking function and contributes to vascular stiffness by regulating SMC proliferation and matrix remodeling.

Published in Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

ISSN: 2047-9980 (Online)
Publisher: Wiley
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the circulatory (Cardiovascular) system
Website: https://www.ahajournals.org/journal/jaha

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