Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice.

Li, J; Zhao, Y; Choi, J; Ting, KK; Coleman, P; Chen, J; Cogger, VC; Wan, L; Shi, Z; Moller, T; Zheng, X; Vadas, MA; Gamble, JR

Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice.

Li, J Zhao, Y Choi, J

Ting, KK Coleman, P Chen, J Cogger, VC Wan, L Shi, Z Moller, T Zheng, X Vadas, MA Gamble, JR

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Publisher:: PUBLIC LIBRARY SCIENCE
Publication Type:: Journal Article
Citation:: PLoS biology, 2020, 18, (6)
Issue Date:: 2020-06-05

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Field	Value	Language
dc.contributor.author	Li, J
dc.contributor.author	Zhao, Y
dc.contributor.author	Choi, J https://orcid.org/0000-0002-0135-8632
dc.contributor.author	Ting, KK
dc.contributor.author	Coleman, P
dc.contributor.author	Chen, J
dc.contributor.author	Cogger, VC
dc.contributor.author	Wan, L
dc.contributor.author	Shi, Z
dc.contributor.author	Moller, T
dc.contributor.author	Zheng, X
dc.contributor.author	Vadas, MA
dc.contributor.author	Gamble, JR
dc.date.accessioned	2020-10-21T05:06:55Z
dc.date.available	2020-05-20
dc.date.available	2020-10-21T05:06:55Z
dc.date.issued	2020-06-05
dc.identifier.citation	PLoS biology, 2020, 18, (6)
dc.identifier.issn	1544-9173
dc.identifier.issn	1545-7885
dc.identifier.uri	http://hdl.handle.net/10453/143431
dc.description.abstract	Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Loss-of-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions. We report here that microRNA-27a (miR-27a), a negative regulator of VE-cadherin, is elevated in ECs isolated from mouse brains developing early CCM lesions and in cultured ECs with CCM1 or CCM2 depletion. Furthermore, we show miR-27a acts downstream of kruppel-like factor (KLF)2 and KLF4, two known key transcription factors involved in CCM lesion development. Using CD5-2 (a target site blocker [TSB]) to prevent the miR-27a/VE-cadherin mRNA interaction, we present a potential therapy to increase VE-cadherin expression and thus rescue the abnormal vascular integrity. In CCM1- or CCM2-depleted ECs, CD5-2 reduces monolayer permeability, and in Ccm1 heterozygous mice, it restores dermal vessel barrier function. In a neonatal mouse model of CCM disease, CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. Furthermore, CD5-2 limits the accumulation of inflammatory cells in the lesion area. Our work has established that VE-cadherin is a potential therapeutic target for normalization of the vasculature and highlights that targeting miR-27a/VE-cadherin interaction by CD5-2 is a potential novel therapy for the devastating disease, CCM.
dc.format	Electronic-eCollection
dc.language	eng
dc.publisher	PUBLIC LIBRARY SCIENCE
dc.relation.ispartof	PLoS biology
dc.relation.isbasedon	10.1371/journal.pbio.3000734
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	06 Biological Sciences, 07 Agricultural and Veterinary Sciences, 11 Medical and Health Sciences
dc.subject.classification	Developmental Biology
dc.subject.mesh	Rhombencephalon
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Humans
dc.subject.mesh	Hemangioma, Cavernous, Central Nervous System
dc.subject.mesh	rhoA GTP-Binding Protein
dc.subject.mesh	Cadherins
dc.subject.mesh	MicroRNAs
dc.subject.mesh	Antigens, CD
dc.subject.mesh	Down-Regulation
dc.subject.mesh	Up-Regulation
dc.subject.mesh	Male
dc.subject.mesh	Kruppel-Like Transcription Factors
dc.subject.mesh	Human Umbilical Vein Endothelial Cells
dc.subject.mesh	Rhombencephalon
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Humans
dc.subject.mesh	Hemangioma, Cavernous, Central Nervous System
dc.subject.mesh	rhoA GTP-Binding Protein
dc.subject.mesh	Cadherins
dc.subject.mesh	MicroRNAs
dc.subject.mesh	Antigens, CD
dc.subject.mesh	Down-Regulation
dc.subject.mesh	Up-Regulation
dc.subject.mesh	Male
dc.subject.mesh	Kruppel-Like Transcription Factors
dc.subject.mesh	Human Umbilical Vein Endothelial Cells
dc.subject.mesh	Animals
dc.subject.mesh	Antigens, CD
dc.subject.mesh	Cadherins
dc.subject.mesh	Down-Regulation
dc.subject.mesh	Hemangioma, Cavernous, Central Nervous System
dc.subject.mesh	Human Umbilical Vein Endothelial Cells
dc.subject.mesh	Humans
dc.subject.mesh	Kruppel-Like Transcription Factors
dc.subject.mesh	Male
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	MicroRNAs
dc.subject.mesh	Rhombencephalon
dc.subject.mesh	Up-Regulation
dc.subject.mesh	rhoA GTP-Binding Protein
dc.title	Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice.
dc.type	Journal Article
utslib.citation.volume	18
utslib.location.activity	United States
utslib.for	06 Biological Sciences
utslib.for	07 Agricultural and Veterinary Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2020-10-21T05:06:32Z
pubs.issue	6
pubs.publication-status	Published
pubs.volume	18
utslib.citation.issue	6

Abstract:

Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Loss-of-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions. We report here that microRNA-27a (miR-27a), a negative regulator of VE-cadherin, is elevated in ECs isolated from mouse brains developing early CCM lesions and in cultured ECs with CCM1 or CCM2 depletion. Furthermore, we show miR-27a acts downstream of kruppel-like factor (KLF)2 and KLF4, two known key transcription factors involved in CCM lesion development. Using CD5-2 (a target site blocker [TSB]) to prevent the miR-27a/VE-cadherin mRNA interaction, we present a potential therapy to increase VE-cadherin expression and thus rescue the abnormal vascular integrity. In CCM1- or CCM2-depleted ECs, CD5-2 reduces monolayer permeability, and in Ccm1 heterozygous mice, it restores dermal vessel barrier function. In a neonatal mouse model of CCM disease, CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. Furthermore, CD5-2 limits the accumulation of inflammatory cells in the lesion area. Our work has established that VE-cadherin is a potential therapeutic target for normalization of the vasculature and highlights that targeting miR-27a/VE-cadherin interaction by CD5-2 is a potential novel therapy for the devastating disease, CCM.

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http://hdl.handle.net/10453/143431