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Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3. No therapies are available for this condi...

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Autores principales: Machuca-Parra, Arturo I., Bigger-Allen, Alexander A., Sanchez, Angie V., Boutabla, Anissa, Cardona-Vélez, Jonathan, Amarnani, Dhanesh, Saint-Geniez, Magali, Siebel, Christian W., Kim, Leo A., D’Amore, Patricia A., Arboleda-Velasquez, Joseph F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551569/
https://www.ncbi.nlm.nih.gov/pubmed/28698285
http://dx.doi.org/10.1084/jem.20161715
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author Machuca-Parra, Arturo I.
Bigger-Allen, Alexander A.
Sanchez, Angie V.
Boutabla, Anissa
Cardona-Vélez, Jonathan
Amarnani, Dhanesh
Saint-Geniez, Magali
Siebel, Christian W.
Kim, Leo A.
D’Amore, Patricia A.
Arboleda-Velasquez, Joseph F.
author_facet Machuca-Parra, Arturo I.
Bigger-Allen, Alexander A.
Sanchez, Angie V.
Boutabla, Anissa
Cardona-Vélez, Jonathan
Amarnani, Dhanesh
Saint-Geniez, Magali
Siebel, Christian W.
Kim, Leo A.
D’Amore, Patricia A.
Arboleda-Velasquez, Joseph F.
author_sort Machuca-Parra, Arturo I.
collection PubMed
description Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3. No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling.
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spelling pubmed-55515692018-02-07 Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL Machuca-Parra, Arturo I. Bigger-Allen, Alexander A. Sanchez, Angie V. Boutabla, Anissa Cardona-Vélez, Jonathan Amarnani, Dhanesh Saint-Geniez, Magali Siebel, Christian W. Kim, Leo A. D’Amore, Patricia A. Arboleda-Velasquez, Joseph F. J Exp Med Research Articles Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3. No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling. The Rockefeller University Press 2017-08-07 /pmc/articles/PMC5551569/ /pubmed/28698285 http://dx.doi.org/10.1084/jem.20161715 Text en © 2017 Machuca-Parra et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Machuca-Parra, Arturo I.
Bigger-Allen, Alexander A.
Sanchez, Angie V.
Boutabla, Anissa
Cardona-Vélez, Jonathan
Amarnani, Dhanesh
Saint-Geniez, Magali
Siebel, Christian W.
Kim, Leo A.
D’Amore, Patricia A.
Arboleda-Velasquez, Joseph F.
Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL
title Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL
title_full Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL
title_fullStr Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL
title_full_unstemmed Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL
title_short Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL
title_sort therapeutic antibody targeting of notch3 signaling prevents mural cell loss in cadasil
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551569/
https://www.ncbi.nlm.nih.gov/pubmed/28698285
http://dx.doi.org/10.1084/jem.20161715
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