Loss of endothelial endoglin promotes high-output heart failure through peripheral arteriovenous shunting driven by VEGF signaling
Author(s)
Type
Journal Article
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.
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.
Date Issued
2020-01-17
Date Acceptance
2019-12-04
Citation
Circulation Research, 2020, 126 (2), pp.243-257
ISSN
0009-7330
Publisher
American Heart Association
Start Page
243
End Page
257
Journal / Book Title
Circulation Research
Volume
126
Issue
2
Copyright Statement
© 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
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
License URL
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000509991900009&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
Subjects
ANGIOGENESIS
arteriovenous malformations
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
CELL PROLIFERATION
endoglin
endothelial cells
EXPRESSION
GROWTH-FACTOR VEGF
Hematology
HEREDITARY HEMORRHAGIC TELANGIECTASIA
hypoxia
Life Sciences & Biomedicine
MOUSE MODELS
Peripheral Vascular Disease
PHASE-I
RECEPTOR
Science & Technology
SOLUBLE ENDOGLIN
vascular diseases
VASCULAR MALFORMATIONS
Publication Status
Published
Date Publish Online
2019-12-06