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1.
Exp Cell Res ; 399(2): 112446, 2021 02 15.
Article in English | MEDLINE | ID: mdl-33422461

ABSTRACT

Communication of vascular cells is essential for the control of organotypic functions of blood vessels. In this context, vascular endothelial cells (EC) act as potent regulators of vascular smooth muscle cell (VSMC) functions such as contraction and relaxation. However, the impact of ECs on the gene expression pattern of VSMCs is largely unknown. Here, we investigated changes of the VSMC transcriptome by utilizing 3D human vascular organoids organized as a core of VSMCs enclosed by a monolayer of ECs. Microarray-based analyses indicated that interaction with ECs for 48 h down-regulates expression of genes in VSMCs controlling rate-limiting steps of the cholesterol biosynthesis such as HMGCR, HMGCS1, DHCR24 and DHCR7. Protein analyses revealed a decrease in the abundance of DHCR24 (24-dehydrocholesterol reductase) and lower cholesterol levels in VSMCs co-cultured with ECs. On the functional level, the blockade of the DHCR24 activity impaired adhesion, migration and proliferation of VSMCs. Collectively, these findings indicate that ECs have the capacity to instruct VSMCs to shut down the expression of DHCR24 thereby limiting their cholesterol biosynthesis, which may support their functional steady state.


Subject(s)
Cholesterol/metabolism , Endothelial Cells/physiology , Muscle, Smooth, Vascular/metabolism , Nerve Tissue Proteins/genetics , Oxidoreductases Acting on CH-CH Group Donors/genetics , Cells, Cultured , Gene Expression Regulation, Enzymologic , Human Umbilical Vein Endothelial Cells , Humans , Lipid Metabolism/genetics , Myocytes, Smooth Muscle/metabolism , Nerve Tissue Proteins/metabolism , Oxidoreductases Acting on CH-CH Group Donors/metabolism
2.
Exp Cell Res ; 388(1): 111782, 2020 03 01.
Article in English | MEDLINE | ID: mdl-31857114

ABSTRACT

Three-dimensional (3D) cell culture conditions are often used to promote the differentiation of human cells as a prerequisite for the study of organotypic functions and environment-specific cellular responses. Here, we assessed the molecular and functional phenotype of vascular smooth muscle cells (VSMCs) cultured as 3D multilayered aggregates. Microarray studies revealed that these conditions decrease the expression of genes associated with cell cycle control and DNA replication and cease proliferation of VSMCs. This was accompanied by a lower activity level of the mitogen-activated protein kinase ERK1/2 and an increase in autocrine TGFß/SMAD2/3-mediated signaling - a determinant of VSMC differentiation. However, inhibition of TGFß signaling did not affect markers of VSMC differentiation such as smooth muscle myosin heavy chain (MYH11) but stimulated pro-inflammatory NFκB-associated gene expression in the first place while decreasing the protein level of NFKB1/p105 and NFKB2/p100 - inhibitors of NFκB transcriptional activity. Moreover, loss of TGFß signaling also revived VSMC proliferation in 3D aggregates. In conclusion, assembly of VSMCs in multilayered aggregates alters their transcriptome to translate the cellular organization into a resting phenotype. In this context, TGFß signaling appears to attenuate cell growth and NFκB-controlled gene expression representing important aspects of VSMC quiescence.


Subject(s)
Cell Differentiation , Gene Expression Regulation, Developmental , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/metabolism , Cell Aggregation , Cell Proliferation , Cells, Cultured , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/physiology , Myosin Heavy Chains/metabolism , NF-kappa B/metabolism , Signal Transduction , Smad Proteins/metabolism , Transcriptome , Transforming Growth Factor beta/metabolism
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