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Differential regulation of angiogenic cellular processes and claudin-5 by histamine and VEGF via PI3K-signaling, transcription factor SNAI2 and interleukin-8.
Laakkonen, Johanna P; Lappalainen, Jari P; Theelen, Thomas L; Toivanen, Pyry I; Nieminen, Tiina; Jauhiainen, Suvi; Kaikkonen, Minna U; Sluimer, Judith C; Ylä-Herttuala, Seppo.
Afiliación
  • Laakkonen JP; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. johanna.p.laakkonen@uef.fi.
  • Lappalainen JP; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Theelen TL; Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, The Netherlands.
  • Toivanen PI; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Nieminen T; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Jauhiainen S; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Kaikkonen MU; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
  • Sluimer JC; Department of Pathology, CARIM, Maastricht University Medical Center, Maastricht, The Netherlands.
  • Ylä-Herttuala S; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Angiogenesis ; 20(1): 109-124, 2017 Feb.
Article en En | MEDLINE | ID: mdl-27873103
ABSTRACT

AIMS:

Histamine and vascular endothelial growth factor A (VEGF) are central regulators in vascular pathologies. Their gene regulation leading to vascular remodeling has remained obscure. In this study, EC regulation mechanisms of histamine and VEGF were compared by RNA sequencing of primary endothelial cells (ECs), functional in vitro assays and in vivo permeability mice model. METHODS AND

RESULTS:

By RNA sequencing, similar transcriptional alterations of genes involved in activation of primary ECs, cell proliferation and adhesion were observed between histamine and VEGF. Seventy-six commonly regulated genes were found, representing ~53% of all VEGF-regulated transcripts and ~26% of all histamine-regulated transcripts. Both factors regulated tight junction formation and expression of pro-angiogenic transcription factors (TFs) affecting EC survival, migration and tube formation. Novel claudin-5 upstream regulatory genes were identified. VEGF was demonstrated to regulate expression of SNAI2, whereas pro-angiogenic TFs NR4A1, MYCN and RCAN1 were regulated by both histamine and VEGF. Claudin-5 was shown to be regulated VEGFR2/PI3K-Akt dependently by VEGF and PI3K-Akt independently by histamine. Interleukin-8 was shown to downregulate claudin-5 by histamine. Additionally, SNAI2, NR4A1 and MYCN were shown to mediate EC survival, migration and tube formation and to regulate expression of claudin-5. Further systemic delivery of VEGF and histamine was shown to induce a fast vascular hyperpermeability response in intact vasculature of C57/Bl6 mice followed by regulation of NR4A1 and MYCN.

CONCLUSIONS:

Our study identifies novel claudin-5 upstream regulatory genes of histamine and VEGF that induce cellular angiogenic processes. Our results increase knowledge of angiogenic EC phenotype and provide novel treatment targets for vascular pathologies.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Histamina / Interleucina-8 / Neovascularización Fisiológica / Fosfatidilinositol 3-Quinasas / Factor A de Crecimiento Endotelial Vascular / Claudina-5 / Factores de Transcripción de la Familia Snail Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Angiogenesis Asunto de la revista: HEMATOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Finlandia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Histamina / Interleucina-8 / Neovascularización Fisiológica / Fosfatidilinositol 3-Quinasas / Factor A de Crecimiento Endotelial Vascular / Claudina-5 / Factores de Transcripción de la Familia Snail Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Angiogenesis Asunto de la revista: HEMATOLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Finlandia