Abstract
BackgroundTGF-β1 is an important angiogenic factor involved in the different aspects of angiogenesis and vessel maintenance. TGF-β signalling is mediated by the TβRII/ALK5 receptor complex activating the Smad2/Smad3 pathway. In endothelial cells TGF-β utilizes a second type I receptor, ALK1, activating the Smad1/Smad5 pathway. Consequently, a perturbance of ALK1, ALK5 or TβRII activity leads to vascular defects. Mutations in ALK1 cause the vascular disorder hereditary hemorrhagic telangiectasia (HHT).MethodsThe identification of ALK1 and not ALK5 regulated genes in endothelial cells, might help to better understand the development of HHT. Therefore, the human microvascular endothelial cell line HMEC-1 was infected with a recombinant constitutively active ALK1 adenovirus, and gene expression was studied by using gene arrays and quantitative real-time PCR analysis.ResultsAfter 24 hours, 34 genes were identified to be up-regulated by ALK1 signalling. Analysing ALK1 regulated gene expression after 4 hours revealed 13 genes to be up- and 2 to be down-regulated. Several of these genes, including IL-8, ET-1, ID1, HPTPη and TEAD4 are reported to be involved in angiogenesis. Evaluation of ALK1 regulated gene expression in different human endothelial cell types was not in complete agreement. Further on, disparity between constitutively active ALK1 and TGF-β1 induced gene expression in HMEC-1 cells and primary HUVECs was observed.ConclusionGene array analysis identified 49 genes to be regulated by ALK1 signalling and at least 14 genes are reported to be involved in angiogenesis. There was substantial agreement between the gene array and quantitative real-time PCR data. The angiogenesis related genes might be potential HHT modifier genes. In addition, the results suggest endothelial cell type specific ALK1 and TGF-β signalling.
Highlights
transforming growth factor (TGF)-β1 is an important angiogenic factor involved in the different aspects of angiogenesis and vessel maintenance
Gene array analysis identified 49 genes to be regulated by ALK1 signalling and at least 14 genes are reported to be involved in angiogenesis
We found substantial agreement between the gene array and quantitative real-time-polymerase chain reaction (qRT-PCR) data, but there were a number of disparate results regarding TGF-β induced signalling and constitutively active receptor signalling depending on the endothelial cell type
Summary
TGF-β1 is an important angiogenic factor involved in the different aspects of angiogenesis and vessel maintenance. Vascular development and homeostasis are regulated by a number of cytokines including members of the transforming growth factor-beta (TGF-β) superfamily that resemble a group of structurally related secreted polypeptides that regulate numerous cellular activities including proliferation, differentiation, migration, extracellular matrix deposition and apoptosis [1,2] This family consists of over 35 cytokines that include TGF-β1, -β2 and -β3, as well as activins, inhibins, nodals and the large group of bone morphogenetic proteins (BMPs). ALK1, a type I receptor for TGF-β1 and -β3 [6,18], activates the BMP signalling pathway by phosphorylating Smad1/5 [19,20] Both endoglin and ALK1 are predominantly expressed by endothelial cells. Heterozygous endoglin as well as ALK1 mice are viable, but a percentage of those develop a phenotype similar to that observed in HHT patients [25,26]
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