干旱区生态环境知识资源中心(Arid): Desert Hedgehog-Driven Endothelium Integrity Is Enhanced by Gas1 (Growth Arrest-Specific 1) but Negatively Regulated by Cdon (Cell Adhesion Molecule-Related/Downregulated by Oncogenes)

Arid

DOI	10.1161/ATVBAHA.120.314441
	Desert Hedgehog-Driven Endothelium Integrity Is Enhanced by Gas1 (Growth Arrest-Specific 1) but Negatively Regulated by Cdon (Cell Adhesion Molecule-Related/Downregulated by Oncogenes)
	Chapouly, Candice; Hollier, Pierre-Louis; Guimbal, Sarah; Cornuault, Lauriane; Gadeau, Alain-Pierre; Renault, Marie-Ange
通讯作者	Renault, MA
来源期刊	ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
ISSN	1079-5642
EISSN	1524-4636
出版年	2020
卷号	40 期号:12 页码:E336-E349
英文摘要	Objective: Evidences accumulated within the past decades identified hedgehog signaling as a new regulator of endothelium integrity. More specifically, we recently identified Dhh (desert hedgehog) as a downstream effector of Klf2 (Kruppel-like factor 2) in endothelial cells (ECs). The purpose of this study is to investigate whether hedgehog coreceptors Gas1 (growth arrest-specific 1) and Cdon (cell adhesion molecule-related/downregulated by oncogenes) may be used as therapeutic targets to modulate Dhh signaling in ECs. Approach and Results: We demonstrated that both Gas1 and Cdon are expressed in adult ECs and relied on either siRNAs- or EC-specific conditional knockout mice to investigate their role. We found that Gas1 deficiency mainly phenocopies Dhh deficiency especially by inducing VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) overexpression while Cdon deficiency has opposite effects by promoting endothelial junction integrity. At a molecular level, Cdon prevents Dhh binding to Ptch1 (patched-1) and thus acts as a decoy receptor for Dhh, while Gas1 promotes Dhh binding to Smo (smoothened) and as a result potentiates Dhh effects. Since Cdon is upregulated in ECs treated by inflammatory cytokines, including TNF (tumor necrosis factor)-alpha and Il (interleukin)-1 beta, we then tested whether Cdon inhibition would promote endothelium integrity in acute inflammatory conditions and found that both fibrinogen and IgG extravasation were decreased in association with an increased Cdh5 (cadherin-5) expression in the brain cortex of EC-specific Cdon knockout mice administered locally with Il-1 beta. Conclusions: Altogether, these results demonstrate that Gas1 is a positive regulator of Dhh in ECs while Cdon is a negative regulator. Interestingly, Cdon blocking molecules may then be used to promote endothelium integrity, at least in inflammatory conditions.
英文关键词	cytokines endothelial cells endothelium hedgehogs therapeutics
类型	Article
语种	英语
开放获取类型	Green Submitted, Bronze, Green Published
收录类别	SCI-E
WOS记录号	WOS:000592297300003
WOS关键词	PATHWAY ; ANGIOGENESIS ; MODEL ; BOC
WOS类目	Hematology ; Peripheral Vascular Disease
WOS研究方向	Hematology ; Cardiovascular System & Cardiology
资源类型	期刊论文
条目标识符	http://119.78.100.177/qdio/handle/2XILL650/327633
作者单位	[Chapouly, Candice; Hollier, Pierre-Louis; Guimbal, Sarah; Cornuault, Lauriane; Gadeau, Alain-Pierre; Renault, Marie-Ange] Univ Bordeaux, INSERM, Biol Cardiovasc Dis, U1034, F-33604 Pessac, France
推荐引用方式 GB/T 7714	Chapouly, Candice,Hollier, Pierre-Louis,Guimbal, Sarah,et al. Desert Hedgehog-Driven Endothelium Integrity Is Enhanced by Gas1 (Growth Arrest-Specific 1) but Negatively Regulated by Cdon (Cell Adhesion Molecule-Related/Downregulated by Oncogenes)[J],2020,40(12):E336-E349.
APA	Chapouly, Candice,Hollier, Pierre-Louis,Guimbal, Sarah,Cornuault, Lauriane,Gadeau, Alain-Pierre,&Renault, Marie-Ange.(2020).Desert Hedgehog-Driven Endothelium Integrity Is Enhanced by Gas1 (Growth Arrest-Specific 1) but Negatively Regulated by Cdon (Cell Adhesion Molecule-Related/Downregulated by Oncogenes).ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY,40(12),E336-E349.
MLA	Chapouly, Candice,et al."Desert Hedgehog-Driven Endothelium Integrity Is Enhanced by Gas1 (Growth Arrest-Specific 1) but Negatively Regulated by Cdon (Cell Adhesion Molecule-Related/Downregulated by Oncogenes)".ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 40.12(2020):E336-E349.