The role of Src-homology 2 domain containing tyrosine phosphatase 2 in growth factor dependent endothelial signalling and angiogenesis

Mannell, Hanna (2007): The role of Src-homology 2 domain containing tyrosine phosphatase 2 in growth factor dependent endothelial signalling and angiogenesis. Dissertation, LMU München: Faculty of Chemistry and Pharmacy

Abstract

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in proliferation, survival and sprouting of human microvascular- and umbilical vein endothelial cells (HMEC, HUVEC) using antisense oligonucleotides (AS-ODN) and a pharmacological SHP-2 inhibitor (PtpI IV). Knock-down of SHP-2 decreased bFGF and PDGF dependent endothelial cell proliferation (p<0.01; n=12) as compared to nonsense oligonucleotide (NS-ODN) treatment. Cell cycle analysis by flow cytometric propidium iodide staining (p<0.01, n=6) and subsequent Annexin V staining (p<0.05, n=9) revealed a significantly higher number of apoptotic cells following SHP-2 AS-ODN transfection. Furthermore, inhibition of SHP-2 significantly impaired the formation of capillary like structures as well as new vessel sprouting in Matrigel embedded mouse aortic rings ex vivo. Finally, this was associated with a decreased phosphorylation of PI3-Kinase, Akt and ERK1/2. Our results indicate that SHP-2 promotes endothelial cell survival and proliferation, possibly by growth factor dependent PI3-K and MAP kinase activation, and is necessary for new vessel formation. These observations suggest SHP-2 to be a key enzyme in the control of angiogenesis.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: SHP-2, angiogenesis, endothelial cells, phosphatase
• Subjects: 500 Natural sciences and mathematics; 500 Natural sciences and mathematics > 540 Chemistry and allied sciences
• Faculties: Faculty of Chemistry and Pharmacy
• Language: English
• Date of oral examination: 24. May 2007
• 1. Referee: Wagner, Ernst
• Signature of the printed copy: 0001/UMC 16306