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

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

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Item Type: Article
Status: Published
Journal or Publication Title: PLOS Biology
Date: 5 June 2020
Subjects: Fields of Research > 11 MEDICAL AND HEALTH SCIENCES > 1102 CARDIORESPIRATORY MEDICINE AND HAEMATOLOGY > 110201 Cardiology (incl. Cardiovascular Diseases)
11 MEDICAL AND HEALTH SCIENCES > 1102 CARDIORESPIRATORY MEDICINE AND HAEMATOLOGY > 110201 Cardiology (incl. Cardiovascular Diseases)
Divisions: Vascular Biology
Depositing User: Mr Nick Keilar
Identification Number: 10.1371/journal.pbio.3000734
Date Deposited: 31 Jul 2020 04:41
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.

Creators:
Creators
Email
Li, Jia
UNSPECIFIED
Zhao, Yang
UNSPECIFIED
Ting, Ka Ka
UNSPECIFIED
Coleman, Paul
UNSPECIFIED
Chen, Jinbiao
UNSPECIFIED
Cogger, Victoria
UNSPECIFIED
Wan, Li
UNSPECIFIED
Shi, Zhongsong
UNSPECIFIED
Moller, Thorleif
UNSPECIFIED
Zheng, Xiangjian
UNSPECIFIED
Vadas, Mathew
UNSPECIFIED
Gamble, Jennifer
UNSPECIFIED
Last Modified: 31 Jul 2020 04:41
URI: https://eprints.centenary.org.au/id/eprint/5

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