Abnormalities in the Von Willebrand-Angiopoietin Axis Contribute to Dysregulated Angiogenesis and Angiodysplasia in Children With a Glenn Circulation

Carlo R Bartoli; Samson Hennessy-Strahs; Robert D Dowling; J William Gaynor; Andrew C Glatz

doi:10.1016/j.jacbts.2020.12.014

Abnormalities in the Von Willebrand-Angiopoietin Axis Contribute to Dysregulated Angiogenesis and Angiodysplasia in Children With a Glenn Circulation

JACC Basic Transl Sci. 2021 Mar 22;6(3):222-235. doi: 10.1016/j.jacbts.2020.12.014. eCollection 2021 Mar.

Authors

Carlo R Bartoli^{1

2}, Samson Hennessy-Strahs^{1

2}, Robert D Dowling³, J William Gaynor², Andrew C Glatz^{4

5

6}

Affiliations

¹ Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
² Department of Cardiothoracic Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³ Division of Cardiac Surgery, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
⁴ Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁵ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Philadelphia, Pennsylvania, USA.
⁶ Center for Pediatric Clinical Effectiveness, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Abstract

Children with a bidirectional superior cavopulmonary (Glenn) circulation develop angiodysplasia and pulmonary arteriovenous malformations (AVMs). The von Willebrand factor (vWF)-angiopoietin axis plays a major role in AVM formation in multiple diseases. We observed derangements in global angiogenic signaling, vWF metabolism, angiopoietins, and in vitro angiogenesis in children with a Glenn circulation versus controls and within Glenn pulmonary versus systemic circulations. These findings support the novel hypothesis that abnormalities in the vWF-angiopoietin axis may dysregulate angiogenesis and contribute to Glenn pulmonary AVMs. The vWF-angiopoietin axis may be a target to correct angiogenic imbalance in Glenn patients, for whom no targeted therapy exists.

Keywords: ADAMTS-13, a disintegrin and metalloproteinase thrombospondin (motif) #13; AVM, arteriovenous malformation; EBM, endothelial basal media; EGM, endothelial growth media; Glenn; HUVEC, human umbilical vein endothelial cell; IVC, inferior vena cava; LVAD, left ventricular assist device; PA, pulmonary artery; SVC, superior vena cava; angiogenesis; angiopoietin; arteriovenous malformation; vWF, von Willebrand factor; von Willebrand factor.