Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signaling

被引:45
作者
Tual-Chalot, Simon [3 ]
Garcia-Collado, Maria [5 ]
Redgrave, Rachael E. [3 ]
Singh, Esha [3 ]
Davison, Benjamin [1 ,3 ]
Park, Catherine [3 ]
Lin, Hua [3 ]
Luli, Saimir [4 ]
Jin, Yi [2 ,5 ]
Wang, Yixin [5 ]
Lawrie, Allan [6 ]
Jakobsson, Lars [5 ]
Arthur, Helen M. [3 ]
机构
[1] Castle Hill Hosp, Cottingham, England
[2] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden
[3] Newcastle Univ, Fac Med Sci, Biosci Inst, Newcastle Upon Tyne, Tyne & Wear, England
[4] Newcastle Univ, Preclin Vivo Imaging Facil, Fac Med Sci, Newcastle Upon Tyne, Tyne & Wear, England
[5] Karolinska Inst, Solna, Sweden
[6] Univ Sheffield, Dept Infect Immun & Cardiovasc Dis, Sheffield, S Yorkshire, England
基金
瑞典研究理事会;
关键词
arteriovenous malformations; endoglin; endothelial cells; hypoxia; vascular diseases; HEREDITARY HEMORRHAGIC TELANGIECTASIA; GROWTH-FACTOR VEGF; SOLUBLE ENDOGLIN; VASCULAR MALFORMATIONS; CELL PROLIFERATION; MOUSE MODELS; PHASE-I; EXPRESSION; RECEPTOR; ANGIOGENESIS;
D O I
10.1161/CIRCRESAHA.119.315974
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:243 / 257
页数:15
相关论文
共 58 条
[1]   ALK1 Loss Results in Vascular Hyperplasia in Mice and Humans Through PI3K Activation [J].
Alsina-Sanchis, Elisenda ;
Garcia-Ibanez, Yaiza ;
Figueiredo, Ana M. ;
Riera-Domingo, Carla ;
Figueras, Agnes ;
Matias-Guiu, Xavier ;
Casanovas, Oriol ;
Botella, Luisa M. ;
Pujana, Miquel A. ;
Riera-Mestre, Antoni ;
Graupera, Mariona ;
Vinals, Francesc .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2018, 38 (05) :1216-1229
[2]   Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination [J].
Anderberg, Charlotte ;
Cunha, Sara I. ;
Zhai, Zhenhua ;
Cortez, Eliane ;
Pardali, Evangelia ;
Johnson, Jill R. ;
Franco, Marcela ;
Paez-Ribes, Marta ;
Cordiner, Ross ;
Fuxe, Jonas ;
Johansson, Bengt R. ;
Goumans, Marie-Jose ;
Casanovas, Oriol ;
ten Dijke, Peter ;
Arthur, Helen M. ;
Pietras, Kristian .
JOURNAL OF EXPERIMENTAL MEDICINE, 2013, 210 (03) :563-579
[3]   Endoglin, an ancillary TGFβ receptor, is required for extraembryonic angiogenesis and plays a key role in heart development [J].
Arthur, HM ;
Ure, J ;
Smith, AJH ;
Renforth, G ;
Wilson, DI ;
Torsney, E ;
Charlton, R ;
Parums, DV ;
Jowett, T ;
Marchuk, DA ;
Burn, J ;
Diamond, AG .
DEVELOPMENTAL BIOLOGY, 2000, 217 (01) :42-53
[4]   Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia [J].
Baeyens, Nicolas ;
Larrivee, Bruno ;
Ola, Roxana ;
Hayward-Piatkowskyi, Brielle ;
Dubrac, Alexandre ;
Huang, Billy ;
Ross, Tyler D. ;
Coon, Brian G. ;
Min, Elizabeth ;
Tsarfati, Maya ;
Tong, Haibin ;
Eichmann, Anne ;
Schwartz, Martin A. .
JOURNAL OF CELL BIOLOGY, 2016, 214 (07) :807-816
[5]   BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain [J].
Bidart, Marie ;
Ricard, Nicolas ;
Levet, Sandrine ;
Samson, Michel ;
Mallet, Christine ;
David, Laurent ;
Subileau, Mariela ;
Tillet, Emmanuelle ;
Feige, Jean-Jacques ;
Bailly, Sabine .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2012, 69 (02) :313-324
[6]   Elevated serum soluble endoglin (sCD105) decreased during extracorporeal elimination therapy for familial hypercholesterolemia [J].
Blaha, Milan ;
Cermanova, Melanie ;
Blaha, Vladimir ;
Jarolim, Petr ;
Andrys, Ctirad ;
Blazek, Martin ;
Maly, Jaroslav ;
Smolej, Lukas ;
Zajic, Jiri ;
Masin, Vladimir ;
Zimova, Renata ;
Rehacek, Vit .
ATHEROSCLEROSIS, 2008, 197 (01) :264-270
[7]   Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients [J].
Blazquez-Medela, Ana M. ;
Garcia-Ortiz, Luis ;
Gomez-Marcos, Manuel A. ;
Recio-Rodriguez, Jose I. ;
Sanchez-Rodriguez, Angel ;
Lopez-Novoa, Jose M. ;
Martinez-Salgado, Carlos .
BMC MEDICINE, 2010, 8
[8]   Liver involvement in hereditary haemorrhagic telangiectasia or Rendu-Osler-Weber disease [J].
Buscarini, E ;
Danesino, C ;
Olivieri, C ;
Lupinacci, G ;
Zambelli, A .
DIGESTIVE AND LIVER DISEASE, 2005, 37 (09) :635-645
[9]   CONGENITAL PELVIC ARTERIOVENOUS-MALFORMATIONS - LONG-TERM FOLLOW-UP IN 2 CASES AND A REVIEW OF THE LITERATURE [J].
CALLIGARO, KD ;
SEDLACEK, TV ;
SAVARESE, RP ;
CARNEVAL, P ;
DELAURENTIS, DA .
JOURNAL OF VASCULAR SURGERY, 1992, 16 (01) :100-108
[10]   Soluble Endoglin Specifically Binds Bone Morphogenetic Proteins 9 and 10 via Its Orphan Domain, Inhibits Blood Vessel Formation, and Suppresses Tumor Growth [J].
Castonguay, Roselyne ;
Werner, Eric D. ;
Matthews, Robert G. ;
Presman, Eleonora ;
Mulivor, Aaron W. ;
Solban, Nicolas ;
Sako, Dianne ;
Pearsall, R. Scott ;
Underwood, Kathryn W. ;
Seehra, Jasbir ;
Kumar, Ravindra ;
Grinberg, Asya V. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (34) :30034-30046