Ruprecht-Karls-Universität Heidelberg Medizinische Fakultät Mannheim
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Research - Endothelial Cells


Principal Investigator: Dr. Torsten Gloe

Description of current research:


Mechanical stress like shear stress caused by high blood flow is one out of many stimuli leading to vascular remodelling in the adult. However, the knowledge about the corresponding cellular signalling cascades is largely incomplete. In the "endothelial cell group" we are particular interested in studying mechanically induced signalling processes in endothelial cells and focus on the regulation of vessel remodelling in adult organisms under physiological and patho-physiological situations.
Shear stress is referred to as the mechanical force induced by the blood flow and acts on the vessel wall surface, whereas wall shear rate describes the deflection of the cell. Shear stress changes with blood flow velocities and represents a physiological stimulus for endothelial cells. Acute elevation of shear stress leads to the production of the vasoactive autacoid nitric oxide (NO). Using this regulatory circuit, the endothelium is enabled to regulate regional blood flow (auto regulation) and pressure without other higher regulatory systems.
In contrast chronically high blood flow (e.g. during physical exercise or by recruitment of collateral vessels after thrombosis) results in an altered expression of certain genes, amongst them we found the endothelial nitric oxide synthase (eNOS). We showed that this induction of gene expression is dependent on specific cells matrix interactions via non-integrin matrix receptors indicating an important regulatory role of the cell-matrix-interaction in mechano-sensitive signalling cascades.
It is also observed that upon persistent high blood flow the vessel wall is remodelled reflecting a vascular adaptation to enhanced mechanical demands in order to maintain a proper functionality.
In the context we are further interested in identifying specific key mediators of induction and progression of those remodelling processes. Recently, we have identified a new proteolytic activity, which is found to be up regulated upon shear stress. Moreover, we found that this activity is necessary for the shear stress dependent release of the angiogenic growth factor FGF-2 whose release mechanism has not been fully understood yet. Additionally, using inhibitors we could show that the FGF-2 release critically depends on the engagement of certain integrins.
Due to enhanced shear stress activated proteases exposure certain matrix fragments accumulate in the extra cellular matrix. In sharp contrast to the intact parental molecules, some of those fragments strongly induced the formation of oxygen radicals (ROS) and in course the induction of apoptosis. We hypothesize that these anti-proliferative and pro-apoptotic effects are representing a negative feed-back-loop preventing an overshooting in vessel remodelling.
Currently we are investigating possible receptors for those distinct matrix fragments in order to get more insight into the regulation of the termination of vascular reorganization.




  • Reference List

     



    Hennig T, Mogensen C, Kirsch J, Pohl U, Gloe T. Shear Stress Induces the Release of an Endothelial Elastase: Role in Integrin ?(v)?(3)-Mediated FGF-2 Release. J Vasc Res. 2011 Jun 17;48(6):453-464.

    Mogensen C, Bergner B, Wallner S, Ritter A, d'Avis S, Ninichuk V, Kameritsch P, Gloe T, Nagel W, Pohl U. Isolation and functional characterization of pericytes derived from hamster skeletal muscle. Acta Physiol (Oxf). 2011 Apr;201(4):413-26.

    Schleifenbaum J, Köhn C, Voblova N, Dubrovska G, Zavarirskaya O, Gloe T, Crean CS, Luft FC, Huang Y, Schubert R, Gollasch M. Systemic peripheral artery relaxation by KCNQ channel openers and hydrogen sulfide. J Hypertens. 2010 Sep;28(9):1875-82.

    Boettcher M, Gloe T, de Wit C. Semiautomatic Quantification of Angiogenesis. J Surg Res. 2010 Jul;162(1):132-9.

    Mannell H, Hellwig N, Gloe T, Plank C, Sohn HY, Groesser L, Walzog B, Pohl U, Krotz F. Inhibition of the tyrosine phosphatase SHP-2 suppresses angiogenesis in vitro and in vivo. J Vasc Res. 2008;45(2):153-63.

    Schulz C, Schäfer A, Stolla M, Kerstan S, Lorenz M, von Brühl ML, Schiemann M, Bauersachs J, Gloe T, Busch DH, Gawaz M, Massberg S. Chemokine fractalkine mediates leukocyte recruitment to inflammatory endothelial cells in flowing whole blood: a critical role for P-selectin expressed on activated platelets. Circulation. 2007 Aug 14;116(7):764-73.

    Krötz F, Keller M, Derflinger S, Schmid H, Gloe T, Bassermann F, Duyster J, Cohen CD, Schuhmann C, Klauss V, Pohl U, Stempfle HU, Sohn HY. Mycophenolate acid inhibits endothelial NAD(P)H oxidase activity and superoxide formation by a Rac1-dependent mechanism. Hypertension. 2007 Jan;49(1):201-8.

    Gonscherowski V, Becker BF, Moroder L, Motrescu E, Gil-Parrado S, Gloe T, Keller M, Zahler S. Calpains: a physiological regulator of the endothelial barrier? Am J Physiol Heart Circ Physiol. 2006 May;290(5):H2035-42.

    Krötz F, Engelbrecht B, Buerkle MA, Bassermann F, Bridell H, Gloe T, Duyster J, Pohl U, Sohn HY. The tyrosine phosphatase, SHP-1, is a negative regulator of endothelial superoxide formation. J Am Coll Cardiol. 2005 May 17;45(10):1700-6.

    Krötz F, Riexinger T, Buerkle MA, Nithipatikom K, Gloe T, Sohn HY, Campbell WB, Pohl U. Membrane-potential-dependent inhibition of platelet adhesion to endothelial cells by epoxyeicosatrienoic acids. Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):595-600.

    Hoffmann A, Gloe T, Pohl U, Zahler S. Nitric oxide enhances de novo formation of endothelial gap junctions. Cardiovasc Res. 2003 Nov 1;60(2):421-30.

    Krötz F, Sohn HY, Gloe T, Plank C, Pohl U. Magnetofection potentiates gene delivery to cultured endothelial cells. J Vasc Res. 2003 Sep-Oct;40(5):425-34.

    Ruyani A, Sudarwati S, Sutasurya LA, Sumarsono SH, Gloe T. The laminin binding protein p40 is involved in inducing limb abnormality of mouse fetuses as the effects of methoxyacetic acid treatment. Toxicol Sci. 2003 Sep;75(1):148-53.

    Sohn HY, Krotz F, Gloe T, Keller M, Theisen K, Klauss V, Pohl U. Differential regulation of xanthine and NAD(P)H oxidase by hypoxia in human umbilical vein endothelial cells. Role of nitric oxide and adenosine. Cardiovasc Res. 2003 Jun 1;58(3):638-46.

    Koczulla R, von Degenfeld G, Kupatt C, Krötz F, Zahler S, Gloe T, Issbrücker K, Unterberger P, Zaiou M, Lebherz C, Karl A, Raake P, Pfosser A, Boekstegers P, Welsch U, Hiemstra PS, Vogelmeier C, Gallo RL, Clauss M, Bals R. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18. J Clin Invest. 2003 Jun;111(11):1665-72.

    Krötz F, de Wit C, Sohn HY, Zahler S, Gloe T, Pohl U, Plank C. Magnetofection--a highly efficient tool for antisense oligonucleotide delivery in vitro and in vivo. Mol Ther. 2003 May;7(5 Pt 1):700-10.

    Sohn HY, Krotz F, Zahler S, Gloe T, Keller M, Theisen K, Schiele TM, Klauss V, Pohl U. Crucial role of local peroxynitrite formation in neutrophil-induced endothelial cell activation. Cardiovasc Res. 2003 Mar;57(3):804-15.

    Zahler S, Hoffmann A, Gloe T, Pohl U. Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration. J Leukoc Biol. 2003 Jan;73(1):118-26.

    Krötz F, Sohn HY, Keller M, Gloe T, Bolz SS, Becker BF, Pohl U. Depolarization of endothelial cells enhances platelet aggregation through oxidative inactivation of endothelial NTPDase. Arterioscler Thromb Vasc Biol. 2002 Dec 1;22(12):2003-9.

    Gloe T, Pohl U. Laminin binding conveys mechanosensing in endothelial cells. News Physiol Sci. 2002 Aug;17:166-9. Review.

    Krötz F, Sohn HY, Gloe T, Zahler S, Riexinger T, Schiele TM, Becker BF, Theisen K, Klauss V, Pohl U. NAD(P)H oxidase-dependent platelet superoxide anion release increases platelet recruitment. Blood. 2002 Aug 1;100(3):917-24.

    Gloe T, Sohn HY, Meininger GA, Pohl U. Shear stress-induced release of basic fibroblast growth factor from endothelial cells is mediated by matrix interaction via integrin alpha(v)beta3. J Biol Chem. 2002 Jun 28;277(26):23453-8.

    Hoffmann A, Gloe T, Pohl U. Hypoxia-induced upregulation of eNOS gene expression is redox-sensitive: a comparison between hypoxia and inhibitors of cell metabolism. J Cell Physiol. 2001 Jul;188(1):33-44.

    Sohn HY, Raff U, Hoffmann A, Gloe T, Heermeier K, Galle J, Pohl U. Differential role of angiotensin II receptor subtypes on endothelial superoxide formation. Br J Pharmacol. 2000 Oct;131(4):667-72.

    Sohn HY, Keller M, Gloe T, Morawietz H, Rueckschloss U, Pohl U. The small G-protein Rac mediates depolarization-induced superoxide formation in human endothelial cells. J Biol Chem. 2000 Jun 23;275(25):18745-50.

    Pohl U, De Wit C, Gloe T. Large arterioles in the control of blood flow: role of endothelium-dependent dilation. Acta Physiol Scand. 2000 Apr;168(4):505-10. Review.

    Sohn HY, Keller M, Gloe T, Crause P, Pohl U. Pitfalls of using lucigenin in endothelial cells: implications for NAD(P)H dependent superoxide formation. Free Radic Res. 2000 Mar;32(3):265-72.

    Sohn HY, Gloe T, Keller M, Schoenafinger K, Pohl U. Sensitive superoxide detection in vascular cells by the new chemiluminescence dye L-012. J Vasc Res. 1999 Nov-Dec;36(6):456-64.

    Gloe T, Riedmayr S, Sohn HY, Pohl U. The 67-kDa laminin-binding protein is involved in shear stress-dependent endothelial nitric-oxide synthase expression. J Biol Chem. 1999 Jun 4;274(23):15996-6002.

    Safi J Jr, Gloe TR, Riccioni T, Kovesdi I, Capogrossi MC. Gene therapy with angiogenic factors: a new potential approach to the
    treatment of ischemic diseases. J Mol Cell Cardiol. 1997 Sep;29(9):2311-25. Review.

    Mühlhauser J, Jones M, Yamada I, Cirielli C, Lemarchand P, Gloe TR, Bewig B, Signoretti S, Crystal RG, Capogrossi MC. Safety and efficacy of in vivo gene transfer into the porcine heart with replication-deficient, recombinant adenovirus vectors. Gene Ther. 1996 Feb;3(2):145-53.

    Cirielli C, Riccioni T, Yang C, Pili R, Gloe T, Chang J, Inyaku K, Passaniti A, Capogrossi MC. Adenovirus-mediated gene transfer of wild-type p53 results in melanoma cell apoptosis in vitro and in vivo. Int J Cancer. 1995 Nov 27;63(5):673-9.

    Okunieff P, Abraham EH, Moini M, Snyder ML, Gloe TR, Capogrossi MC, Ding I. Basic fibroblast growth factor radioprotects bone marrow and not RIF1 tumor. Acta Oncol. 1995;34(3):435-8.

    Neu-Yilik G, Zorbas H, Gloe TR, Raabe HM, Hopp-Christensen TA, Müller PK. Vigilin is a cytoplasmic protein. A study on its expression in primary cells and in established cell lines of different species. Eur J Biochem. 1993 Apr 15;213(2):727-36.

    Henkel B, Schmidt C, Zorbas H, Pöschl E, Gloe TR, Purschke WG, Müller PK. Chicken vigilin gene organization and expression pattern. The domain structure of the protein is reflected by the exon structure. Eur J Biochem. 1992 Oct 1;209(1):321-8.

    Schmidt C, Henkel B, Pöschl E, Zorbas H, Purschke WG, Gloe TR, Müller PK. Complete cDNA sequence of chicken vigilin, a novel protein with amplified and volutionary conserved domains. Eur J Biochem. 1992 Jun 15;206(3):625-34.

     

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