13.5. Microarray Study: Gene Expression in Endothelial Cell Cultures and Intracranial Aneurysms

Public examination of a doctoral dissertation in the field of molecular medicine

Doctoral candidate: MSc Sanna-Kaisa Häkkinen

Time and venue: 13.5.2011 at 12 noon, Tietoteknia Auditorium, Kuopio Campus

DNA microarray technology has proven to be a very useful and important tool in the field of molecular biology. The possibility to measure expression levels of thousands of genes simultaneously has facilitated the research of polygenic diseases. Vascular diseases are the main cause of mortality and morbidity in the western world. Therefore it is necessary to clarify the mechanisms of pathogenesis of these diseases. Large scale gene expression profiling will enhance the development of therapeutic strategies for the treatment of vascular diseases.

Vascular endothelial growth factors (VEGFs) have important roles in the growth, differentiation, and maintenance of blood vessels. They are also involved in many pathological conditions such as in atherosclerosis. The endothelium is a major regulator of vascular tone and remodelling as well as arterial inflammation and thrombosis. Endothelial dysfunction in considered as an early sign of atherosclerosis. In this study the effects of overexpression of one important human VEGF, VEGF-DDNDC, was studied in human vascular endothelial cells (HUVECs) to elucidate the role and significance of VEGF-DDNDC in vascular biology. Intracranial aneurysm (IA) is a life-threatening condition. Rupture of IA causes subarachnoid hemorrhage which is associated with high mortality. It is not known why aneurysms rupture. In this study Affymetrix microarrays was used to analyze the difference in the gene expression of ruptured and unruptured intracranial aneurysms.

Overexpression of VEGF-DDNDC caused activation of three signalling cascades downstream from VEGFR-2 (vascular endothelial growth factor receptor -2) which induces vasodilatation and endothelial survival. Also, upregulation of VEGF-A, neuropilin 2 (NRP2) and stanniocalcin 1(STC1) was evident and it seemed to regulate and amplify the effects of VEGF-DDNDC. In the aneurysm study there was significant upregulation of 686 genes and downregulation of 740 genes in the ruptured aneurysms. Significantly upregulated biological processes included: chemotaxis, leukocyte migration, oxidative stress, vascular remodelling, and extracellular matrix (ECM) degradation.

In HUVECs possible mechanism for VEGF-DDNDC regulation was found that will increase understanding about the biology of VEGF-DDNDC. Especially VEGF-A, NRP2 and STC1 particularly seem to have key roles in VEGF-DDNDC signalling and regulation. In the aneurysm expression analysis, pathways and candidate genes associated to the rupture of human saccular IA (sIA) was identified. The results provide clues to the molecular mechanisms in sIA wall rupture and insight for novel therapeutic strategies to prevent rupture. Gene expression profiling is a convenient and modern research tool that will help us to understand mechanisms behind complex diseases.

The doctoral dissertation of Master of Science Sanna-Kaisa Häkkinen, entitled Microarray Study: Gene Expression in Endothelial Cell Cultures and Intracranial Aneurysms will be examined at the Faculty of Health Sciences. The opponent in the public examination will be Professor Riitta Lahesmaa of the University of Turku and the custos will be Professor Seppo Ylä-Herttuala of the University of Eastern Finland.

Photo available for download at http://www.uef.fi/vaitoskuvat

Publishing year: 2011

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