Constitutive Active Mutant TIE2 Induces Enlarged Vascular Lumen Formation with Loss of Apico-basal Polarity and Pericyte Recruitment

Abstract Abnormalities in controlling key aspects of angiogenesis including vascular cell migration, lumen formation and vessel maturation are hallmarks of vascular anomalies including venous malformation (VM). Gain-of-function mutations in the tyrosine kinase receptor TIE2 can cause VM and induce a...

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Autores principales:	Yuqi Cai, Sandra Schrenk, Jillian Goines, George E. Davis, Elisa Boscolo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d60729f8db694524a763b01f44aa65cc
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spelling	oai:doaj.org-article:d60729f8db694524a763b01f44aa65cc2021-12-02T15:09:19ZConstitutive Active Mutant TIE2 Induces Enlarged Vascular Lumen Formation with Loss of Apico-basal Polarity and Pericyte Recruitment10.1038/s41598-019-48854-22045-2322https://doaj.org/article/d60729f8db694524a763b01f44aa65cc2019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-48854-2https://doaj.org/toc/2045-2322Abstract Abnormalities in controlling key aspects of angiogenesis including vascular cell migration, lumen formation and vessel maturation are hallmarks of vascular anomalies including venous malformation (VM). Gain-of-function mutations in the tyrosine kinase receptor TIE2 can cause VM and induce a ligand-independent hyperactivation of TIE2. Despite these important findings, the TIE2-dependent mechanisms triggering enlarged vascular lesions are not well understood. Herein we studied TIE2 p.L914F, the most frequent mutation identified in VM patients. We report that endothelial cells harboring a TIE2-L914F mutation display abnormal cell migration due to a loss of front-rear polarity as demonstrated by a non-polarized Golgi apparatus. Utilizing a three-dimensional fibrin-matrix based model we show that TIE2-L914F mutant cells form enlarged lumens mimicking vascular lesions present in VM patients, independently of exogenous growth factors. Moreover, these abnormal vascular channels demonstrate a dysregulated expression pattern of apico-basal polarity markers Podocalyxin and Collagen IV. Furthermore, in this system we recapitulated another pathological feature of VM, the paucity of pericytes around ectatic veins. The presented data emphasize the value of this in vitro model as a powerful tool for the discovery of cellular and molecular signals contributing to abnormal vascular development and subsequent identification of novel therapeutic approaches.Yuqi CaiSandra SchrenkJillian GoinesGeorge E. DavisElisa BoscoloNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-12 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yuqi Cai Sandra Schrenk Jillian Goines George E. Davis Elisa Boscolo Constitutive Active Mutant TIE2 Induces Enlarged Vascular Lumen Formation with Loss of Apico-basal Polarity and Pericyte Recruitment
description	Abstract Abnormalities in controlling key aspects of angiogenesis including vascular cell migration, lumen formation and vessel maturation are hallmarks of vascular anomalies including venous malformation (VM). Gain-of-function mutations in the tyrosine kinase receptor TIE2 can cause VM and induce a ligand-independent hyperactivation of TIE2. Despite these important findings, the TIE2-dependent mechanisms triggering enlarged vascular lesions are not well understood. Herein we studied TIE2 p.L914F, the most frequent mutation identified in VM patients. We report that endothelial cells harboring a TIE2-L914F mutation display abnormal cell migration due to a loss of front-rear polarity as demonstrated by a non-polarized Golgi apparatus. Utilizing a three-dimensional fibrin-matrix based model we show that TIE2-L914F mutant cells form enlarged lumens mimicking vascular lesions present in VM patients, independently of exogenous growth factors. Moreover, these abnormal vascular channels demonstrate a dysregulated expression pattern of apico-basal polarity markers Podocalyxin and Collagen IV. Furthermore, in this system we recapitulated another pathological feature of VM, the paucity of pericytes around ectatic veins. The presented data emphasize the value of this in vitro model as a powerful tool for the discovery of cellular and molecular signals contributing to abnormal vascular development and subsequent identification of novel therapeutic approaches.
format	article
author	Yuqi Cai Sandra Schrenk Jillian Goines George E. Davis Elisa Boscolo
author_facet	Yuqi Cai Sandra Schrenk Jillian Goines George E. Davis Elisa Boscolo
author_sort	Yuqi Cai
title	Constitutive Active Mutant TIE2 Induces Enlarged Vascular Lumen Formation with Loss of Apico-basal Polarity and Pericyte Recruitment
title_short	Constitutive Active Mutant TIE2 Induces Enlarged Vascular Lumen Formation with Loss of Apico-basal Polarity and Pericyte Recruitment
title_full	Constitutive Active Mutant TIE2 Induces Enlarged Vascular Lumen Formation with Loss of Apico-basal Polarity and Pericyte Recruitment
title_fullStr	Constitutive Active Mutant TIE2 Induces Enlarged Vascular Lumen Formation with Loss of Apico-basal Polarity and Pericyte Recruitment
title_full_unstemmed	Constitutive Active Mutant TIE2 Induces Enlarged Vascular Lumen Formation with Loss of Apico-basal Polarity and Pericyte Recruitment
title_sort	constitutive active mutant tie2 induces enlarged vascular lumen formation with loss of apico-basal polarity and pericyte recruitment
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/d60729f8db694524a763b01f44aa65cc
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Constitutive Active Mutant TIE2 Induces Enlarged Vascular Lumen Formation with Loss of Apico-basal Polarity and Pericyte Recruitment

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