Tual-Chalot, S., Garcia-Collado, M., Redgrave, R.E. et al. (10 more authors) (2020) Loss of endothelial endoglin promotes high-output heart failure through peripheral arteriovenous shunting driven by VEGF signaling. Circulation Research, 126 (2). pp. 243-257. ISSN 0009-7330
Abstract
Rationale:
ENG (endoglin) is a coreceptor for BMP (bone morphogenetic protein) 9/10 and is strongly expressed in endothelial cells. Mutations in ENG lead to the inherited vascular disorder hereditary hemorrhagic telangiectasia characterized by local telangiectases and larger arteriovenous malformations (AVMs); but how ENG functions to regulate the adult vasculature is not understood.
Objective:
The goal of the work was to determine how ENG maintains vessel caliber in adult life to prevent AVM formation and thereby protect heart function.
Methods and Results:
Genetic depletion of endothelial Eng in adult mice led to a significant reduction in mean aortic blood pressure. There was no evidence of hemorrhage, anemia, or AVMs in major organs to explain the reduced aortic pressure. However, large AVMs developed in the peripheral vasculature intimately associated with the pelvic cartilaginous symphysis—a noncapsulated cartilage with a naturally high endogenous expression of VEGF (vascular endothelial growth factor). The increased blood flow through these peripheral AVMs explained the drop in aortic blood pressure and led to increased cardiac preload, and high stroke volumes, ultimately resulting in high-output heart failure. Development of pelvic AVMs in this region of high VEGF expression occurred because loss of ENG in endothelial cells leads to increased sensitivity to VEGF and a hyperproliferative response. Development of AVMs and associated progression to high-output heart failure in the absence of endothelial ENG was attenuated by targeting VEGF signaling with an anti-VEGFR2 (VEGF receptor 2) antibody.
Conclusions:
ENG promotes the normal balance of VEGF signaling in quiescent endothelial cells to maintain vessel caliber—an essential function in conditions of increased VEGF expression such as local hypoxia or inflammation. In the absence of endothelial ENG, increased sensitivity to VEGF drives abnormal endothelial proliferation in local regions of high VEGF expression, leading to AVM formation and a rapid injurious impact on heart function.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 The Authors. Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited (https://creativecommons.org/licenses/by/4.0/). |
Keywords: | arteriovenous malformations; endoglin; endothelial cells; hypoxia; vascular diseases |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number BRITISH HEART FOUNDATION 33808 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 09 Mar 2020 11:17 |
Last Modified: | 09 Mar 2020 11:17 |
Status: | Published |
Publisher: | Wolters Kluwer Health |
Refereed: | Yes |
Identification Number: | 10.1161/circresaha.119.315974 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:156905 |