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      About Journal of Vascular Research: 1.8 Impact Factor I 3.4 CiteScore I 0.486 Scimago Journal & Country Rank (SJR)

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      The Role of Pericyte Detachment in Vascular Rarefaction

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          Abstract

          Background: Pericytes surround endothelial cells at the perivascular interface. Signaling between endothelial cells and pericytes is crucial for capillary homeostasis, as pericytes stabilize vessels and regulate many microvascular functions. Recently it has been shown that pericytes are able to detach from the vascular wall and contribute to fibrosis by becoming scar-forming myofibroblasts in many organs including the kidney. At the same time, the loss of pericytes within the perivascular compartment results in vulnerable capillaries which are prone to instability, pathological angiogenesis, and, ultimately, rarefaction. Aims: This review will give an overview of pericyte-endothelial cell interactions, summarize the signaling pathways that have been identified to be involved in pericyte detachment from the vascular wall, and present pathological endothelial responses in the context of disease of the kidney.

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          Most cited references75

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          Origin and function of myofibroblasts in kidney fibrosis.

          Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.
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            Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition.

            Fibroblasts are key mediators of fibrosis in the kidney and other organs, but their origin during fibrosis is still not completely clear. Activated fibroblasts likely arise from resident quiescent fibroblasts via epithelial-to-mesenchymal transition and from the bone marrow. Here, we demonstrate that endothelial cells also contribute to the emergence of fibroblasts during kidney fibrosis via the process of endothelial-to-mesenchymal transition (EndMT). We examined the contribution of EndMT to renal fibrosis in three mouse models of chronic kidney disease: (1) Unilateral ureteral obstructive nephropathy, (2) streptozotocin-induced diabetic nephropathy, and (3) a model of Alport renal disease. Approximately 30 to 50% of fibroblasts coexpressed the endothelial marker CD31 and markers of fibroblasts and myofibroblasts such as fibroblast specific protein-1 and alpha-smooth muscle actin. Endothelial lineage tracing using Tie2-Cre;R26R-stop-EYFP transgenic mice further confirmed the presence of EndMT-derived fibroblasts. Collectively, our results demonstrate that EndMT contributes to the accumulation of activated fibroblasts and myofibroblasts in kidney fibrosis and suggest that targeting EndMT might have therapeutic potential.
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              Therapy for fibrotic diseases: nearing the starting line.

              Fibrosis, or the accumulation of extracellular matrix molecules that make up scar tissue, is a common feature of chronic tissue injury. Pulmonary fibrosis, renal fibrosis, and hepatic cirrhosis are among the more common fibrotic diseases, which in aggregate represent a huge unmet clinical need. New appreciation of the common features of fibrosis that are conserved among tissues has led to a clearer understanding of how epithelial injury provokes dysregulation of cell differentiation, signaling, and protein secretion. At the same time, discovery of tissue-specific features of fibrogenesis, combined with insights about genetic regulation of fibrosis, has laid the groundwork for biomarker discovery and validation, and the rational identification of mechanism-based antifibrotic drugs. Together, these advances herald an era of sustained focus on translating the biology of fibrosis into meaningful improvements in quality and length of life in patients with chronic fibrosing diseases.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2014
                October 2014
                03 September 2014
                : 51
                : 4
                : 247-258
                Affiliations
                aDivision of Vascular and Endovascular Surgery, Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany; bDivision of Nephrology, Center for Lung Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Wash., USA
                Author notes
                *Dr. Claudia Schrimpf, GMP and Tissue Engineering Laboratory, Division of Vascular and Endovascular Surgery, Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Carl-Neuberg-Strasse 1, DE-30625 Hannover (Germany), E-Mail Schrimpf.Claudia@mh-hannover.de, Dr. Jeremy S. Duffield, Division of Nephrology, Center for Lung Biology and Institute for Stem Cell and Regenerative Medicine University of Washington, Seattle, WA 98109 (USA), E-Mail jeremysd@uw.edu
                Article
                365149 J Vasc Res 2014;51:247-258
                10.1159/000365149
                4476411
                25195856
                fdc6327b-0f4d-47b4-b491-97d7b667800c
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 02 November 2013
                : 07 June 2014
                Page count
                Figures: 3, Tables: 1, Pages: 12
                Categories
                Review

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Pericytes,Endothelial cells,Pericyte-endothelial interaction,Fibrosis,Microcirculation

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