Mesenchymal Behavior of the Endothelium Promoted by SMAD6 Downregulation Is Associated With Brain Arteriovenous Malformation Microhemorrhage.

Adult Arteriovenous Fistula / complications Cerebral Hemorrhage / etiology Down-Regulation Endothelial Cells / metabolism Female Humans Intracranial Arteriovenous Malformations / complications Male Middle Aged Signal Transduction / physiology Smad6 Protein / metabolism Transforming Growth Factor beta / metabolism
arteriovenous malformations downregulation endothelial cells phenotype umbilical veins

Journal

Stroke
ISSN: 1524-4628
Titre abrégé: Stroke
Pays: United States
ID NLM: 0235266

Informations de publication

Date de publication:
07 2020
Historique:
pubmed: 4 6 2020
medline: 5 11 2020
entrez: 4 6 2020
Statut: ppublish

Résumé

In unruptured brain arteriovenous malformations (bAVMs), microhemorrhage portends a higher risk of future rupture and may represent a transitional state along the continuum of destabilization. Exploration of the molecular and cellular mechanisms of microhemorrhage will provide a possible target for medical treatment to prevent bAVM bleeding. We performed RNA sequencing analysis on 34 unruptured bAVM surgical samples. Functional pathway analysis was performed to identify potential signals associated with the microhemorrhagic phenotype. Candidate gene was then investigated in bAVM specimens by immunohistochemical staining. Several functional assays were used to investigate the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells. Then, Masson trichrome staining and immunofluorescence staining were used to evaluate the phenotypic and molecular changes in bAVM tissue. Via RNA sequencing, we identified differential gene expression between 18 microhemorrhagic bAVMs and 16 nonmicrohemorrhagic bAVMs. TGFβ (transforming growth factor-beta)/BMP (bone morphogenetic protein) signaling was associated with the bAVM microhemorrhage group when SMAD6 (SMAD family member 6) was downregulated. Immunohistochemical staining showed that the vascular endothelium of microhemorrhagic bAVMs exhibited decreased SMAD6 expression. Functional assays revealed that SMAD6 downregulation promoted the formation of endothelial cell tubes with deficient cell-cell junctions and facilitated the acquisition of mesenchymal behavior by endothelial cells. Masson trichrome and immunofluorescence staining demonstrated that mesenchymal phenotype of endothelial cells is promoted in microhemorrhagic bAVMs. TGFβ/BMP signaling mediated by SMAD6 in vascular endothelial cells is associated with microhemorrhagic bAVMs, and mesenchymal behavior of endothelial cells induced by SMAD6 downregulation is related with bAVM microhemorrhage.

Sections du résumé

BACKGROUND AND PURPOSE
In unruptured brain arteriovenous malformations (bAVMs), microhemorrhage portends a higher risk of future rupture and may represent a transitional state along the continuum of destabilization. Exploration of the molecular and cellular mechanisms of microhemorrhage will provide a possible target for medical treatment to prevent bAVM bleeding.
METHODS
We performed RNA sequencing analysis on 34 unruptured bAVM surgical samples. Functional pathway analysis was performed to identify potential signals associated with the microhemorrhagic phenotype. Candidate gene was then investigated in bAVM specimens by immunohistochemical staining. Several functional assays were used to investigate the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells. Then, Masson trichrome staining and immunofluorescence staining were used to evaluate the phenotypic and molecular changes in bAVM tissue.
RESULTS
Via RNA sequencing, we identified differential gene expression between 18 microhemorrhagic bAVMs and 16 nonmicrohemorrhagic bAVMs. TGFβ (transforming growth factor-beta)/BMP (bone morphogenetic protein) signaling was associated with the bAVM microhemorrhage group when SMAD6 (SMAD family member 6) was downregulated. Immunohistochemical staining showed that the vascular endothelium of microhemorrhagic bAVMs exhibited decreased SMAD6 expression. Functional assays revealed that SMAD6 downregulation promoted the formation of endothelial cell tubes with deficient cell-cell junctions and facilitated the acquisition of mesenchymal behavior by endothelial cells. Masson trichrome and immunofluorescence staining demonstrated that mesenchymal phenotype of endothelial cells is promoted in microhemorrhagic bAVMs.
CONCLUSIONS
TGFβ/BMP signaling mediated by SMAD6 in vascular endothelial cells is associated with microhemorrhagic bAVMs, and mesenchymal behavior of endothelial cells induced by SMAD6 downregulation is related with bAVM microhemorrhage.

Identifiants

DOI: 10.1161/STROKEAHA.120.030046 PMID: 32486965
pubmed: 32486965
doi: 10.1161/STROKEAHA.120.030046
doi:

Substances chimiques

SMAD6 protein, human 0
Smad6 Protein 0
Transforming Growth Factor beta 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2197-2207

Auteurs

Weilun Fu (W)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).

Ran Huo (R)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).

Zihan Yan (Z)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).

Hongyuan Xu (H)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).

Hao Li (H)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).

Yuming Jiao (Y)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).

Linjian Wang (L)

Savaid Medical School, University of the Chinese Academy of Sciences, Beijing (L.W., J.Z.).

Jiancong Weng (J)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).

Jie Wang (J)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).

Shuo Wang (S)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).

Yong Cao (Y)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
Beijing Neurosurgical Institute, Capital Medical University, China (Y.C.).

Jizong Zhao (J)

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
China National Clinical Research Center for Neurological Diseases, Beijing (W.F., R.H., Z.Y, H.X., H.L., Y.J., J. Weng, J. Wang, S.W., Y.C., J.Z.).
Savaid Medical School, University of the Chinese Academy of Sciences, Beijing (L.W., J.Z.).

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Mesenchymal Behavior of the Endothelium...
questionsmedicales.fr › États, signes et symptômes pathologiques › États anatomopathologiques › Fistule › Fistule vasculaire › Fistule artérioveineuse › Mesenchymal Behavior of the Endothelium...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Hémorragie › Hémorragies intracrâniennes › Hémorragie cérébrale › Mesenchymal Behavior of the Endothelium...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation négative › Mesenchymal Behavior of the Endothelium...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules endothéliales › Mesenchymal Behavior of the Endothelium...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Mesenchymal Behavior of the Endothelium...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations du système nerveux › Malformations vasculaires du système nerveux central › Malformations artérioveineuses intracrâniennes › Mesenchymal Behavior of the Endothelium...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Mesenchymal Behavior of the Endothelium...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Mesenchymal Behavior of the Endothelium...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines Smad › Protéine Smad6 › Mesenchymal Behavior of the Endothelium...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la superfamille du TGF bêta › Facteur de croissance transformant bêta › Mesenchymal Behavior of the Endothelium...