ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-β and constitutively active receptor induced gene expression

被引：35

作者：

Lux A. ^{[1
,2
,8
]}

Salway F. ^{[3
]}

Dressman H.K. ^{[4
,5
]}

Kröner-Lux G. ^{[6
]}

Hafner M. ^{[2
,8
]}

Day P.J.R. ^{[3
]}

Marchuk D.A. ^{[4
]}

Garland J. ^{[7
]}

机构：

[1] University Hospital Mannheim

[2] Institute of Molecular and Cell Biology, University of Applied Sciences Mannheim, 68163 Mannheim

[3] Centre for Integrated Genomic Medical Research, University of Manchester

[4] Department of Molecular Genetics and Microbiology, DUMC, Durham

[5] Duke Institute for Genome Sciences and Policy, DUMC, Durham

[6] PROGEN Biotechnik GmbH, 69123 Heidelberg

[7] Manchester Cardiovascular Research Group, University of Manchester, Department of Medicine

[8] University of Applied Sciences Mannheim, 68163 Mannheim

来源：

BMC Cardiovascular Disorders | / 6卷 / 1期

关键词：

Gene Array; Recombinant Adenovirus; Hereditary Hemorrhagic Telangiectasia; Hereditary Haemorrhagic Telangiectasia; Hereditary Hemorrhagic Telangiectasia Patient;

D O I：

10.1186/1471-2261-6-13

中图分类号：

学科分类号：

摘要：

TGF-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, ALKI, activating the SmadI/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). Methods: The 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 HIMEC-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. Results: After 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-I, IDI, 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. Conclusion: Gene 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. © 2006 Lux et al; licensee BioMed Central Ltd.

引用

共 93 条

[1] Massague J., Blain S.W., Lo R.S., TGFbeta signaling in growth control, cancer, and heritable disorders, Cell, 103, pp. 295-309, (2000)
[2] ten Dijke P., Hill C.S., New insights into TGF-beta-Smad signalling, Trends Biochem Sci, 29, pp. 265-273, (2004)
[3] Blobe G.C., Schiemann W.P., Lodish H.F., Role of transforming growth factor beta in human disease, N Engl J Med, 342, pp. 1350-1358, (2000)
[4] Shi Y., Massague J., Mechanisms of TGF-beta signaling from cell membrane to the nucleus, Cell, 113, pp. 685-700, (2003)
[5] Pepper M.S., Transforming growth factor-beta. vasculogenesis, angiogenesis, and vessel wall integrity, Cytokine Growth Factor Rey, 8, pp. 21-43, (1997)
[6] Goumans M.J., Valdimarsdottir G., Itoh S., Rosendahl A., Sideras P., ten Dijke P., Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors, Embo J, 21, pp. 1743-1753, (2002)
[7] Pepper M.S., Vassalli J.D., Orci L., Montesano R., Biphasic effect of transforming growth factor-beta I on in vitro angiogenesis, Exp Cell Res, 204, pp. 356-363, (1993)
[8] Gajdusek C.M., Luo Z., Mayberg M.R., Basic fibroblast growth factor and transforming growth factor beta-I: Synergistic mediators of angiogenesis in vitro, J Cell Physiol, 157, pp. 133-144, (1993)
[9] van den Driesche S., Mummery C.L., Westermann C.J., Hereditary hemorrhagic telangiectasia: An update on transforming growth factor beta signaling in vasculogenesis and angiogenesis, Cardiovasc Res, 58, pp. 20-31, (2003)
[10] Marchuk D.A., Lux A., Hereditary Hemorrhagic Telangiectasia, The Metabolic & Molecular Bases of Inherited Disease, 4, pp. 5419-55431, (2001)

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