title: Proliferation status defines functional properties of endothelial cells.
abstract: Homeostasis of solid tissue is characterized by a low proliferative activity of differentiated cells while special conditions like tissue damage induce regeneration and proliferation. For some cell types it has been shown that various tissue-specific functions are missing in the proliferating state, raising the possibility that their proliferation is not compatible with a fully differentiated state. While endothelial cells are important players in regenerating tissue as well as in the vascularization of tumors, the impact of proliferation on their features remains elusive. To examine cell features in dependence of proliferation, we established human endothelial cell lines in which proliferation is tightly controlled by a doxycycline-dependent, synthetic regulatory unit. We observed that uptake of macromolecules and establishment of cell-cell contacts was more pronounced in the growth-arrested state. Tube-like structures were formed in vitro in both proliferating and non-proliferating conditions. However, functional vessel formation upon transplantation into immune-compromised mice was restricted to the proliferative state. Kaposi's sarcoma-associated herpes virus (KSHV) infection resulted in reduced expression of endothelial markers. Upon transplantation of infected cells, drastic differences were observed: proliferation arrested cells acquired a high migratory activity while the proliferating counterparts established a tumor-like phenotype, similar to Kaposi Sarcoma lesions. The study gives evidence that proliferation governs endothelial functions. This suggests that several endothelial functions are differentially expressed during angiogenesis. Moreover, since proliferation defines the functional properties of cells upon infection with KSHV, this process crucially affects the fate of virus-infected cells.
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany.|Experimental Cardiology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lipps
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany.|Gomal Center of Biochemistry and Biotechnology, Gomal University, D. I. Khan, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Badar
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Milada
authors.initials: M
authors.lastname: Butueva
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Dubich
authors.affiliation: Institute for Virology, Medical University in Hannover, Hannover, Germany.|Value Edge Research Services, Noida, India.
authors.forename: Vivek Vikram
authors.initials: VV
authors.lastname: Singh
authors.affiliation: Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rau
authors.affiliation: Rudolf-Buchheim Institute for Pharmacology, Schubertstraße 81, 35392, Giessen, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Weber
authors.affiliation: Rudolf-Buchheim Institute for Pharmacology, Schubertstraße 81, 35392, Giessen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Köster
authors.affiliation: Inscreenex GmbH, Inhoffenstr. 7, 38124, Brunswick, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: May
authors.affiliation: Institute for Virology, Medical University in Hannover, Hannover, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Schulz
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Hauser
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124, Braunschweig, Germany. dagmar.wirth@helmholtz-hzi.de.|Institute for Experimental Hematology, Medical University in Hannover, Hannover, Germany. dagmar.wirth@helmholtz-hzi.de.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wirth
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D051929:CD146 Antigen / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation; D000071063:Endoglin / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism* / Q000637:transplantation; D020869:Gene Expression Profiling; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009569:Nitric Oxide / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000209:etiology; D015854:Up-Regulation
chemical_list: D018952:Antigens, CD34; D051929:CD146 Antigen; D000071063:Endoglin; D009569:Nitric Oxide
keywords: Endothelial cells; Humanized mouse model; KSHV; Proliferation; Vessel formation