Vascular Signaling

Research Interest

Our new established lab at the Medical Faculty Mannheim of the University of Heidelberg studies endothelial cells to understand the origin, development, differentiation as well as the regulation of the vascular system under physiological and pathophysiological conditions.

Mesodermal cells are the origin of the so-called hemangioblast, which are precursors for either endothelial cells or blood cells. Then, primitive endothelial cells develop and differentiate later on to a complex vascular network. The aim of our lab is to identify and characterize genes that regulate fate and function of different endothelial cell types and how these genes are involved in cardiovascular diseases. To accomplish our goals we use a broad spectrum of molecular, biochemical, cell biological as well as genetic methods.

Our long-term goal is to delineate signaling and genetic pathways for the formation and function of endothelial cells and based on this information to develop new therapeutical strategies to treat human vascular diseases.

Current Projects:

¨ Analysis of signaling pathways that regulate endothelial cell differentiation and function

¨ Genetic dissection of endothelial differentiation in human endothelial cells

¨ Genetic dissection of endothelial development in mice and zebrafish

¨ Identification and functional characterization of novel genes regulating cardiovascular development/function and tumor development

Please contact Dr. Jens Kroll for further information: kroll(at)angiogenese.de

=> CV of PD Dr. Jens Kroll

VEGF-driven phosphorylation of VEGF receptor KDR in endothelial cells (see Kroll et al., JBC, 1997).

Endothelial expression of BTB-kelch protein KLHL6 in mice (see Kroll at al., MCB, 2005).

Cardiac expression of BTB-kelch protein KLHL6 in mice (see Kroll at al., MCB, 2005).

Vascularization of R30C cells-dervied tumor in mice (see Kretna et al., Cancer Research, 2006).

Golgi complex localization of BTB-kelch protein LZTR-1 in human smooth muscle cells (see Nacak at al., JBC, 2006).

Co-localization of BTB-kelch protein KLEIP (green) with actin (red) in endothelial cells (see Nacak at al., Circulation Research, 2007).

Publications

- Research papers -

Würl P, Taubert H, Bache M, Kroll J, Meye A, Berger D, Siermann A, Holzhausen HJ, Hinze R, Schmidt H, and Rath FW. Frequent occurrence of p53 mutations in rhabdomyosarcoma and leiomyosarcoma, but not in fibrosarcoma and malignant neural tumors. Int J Cancer 69: 317-323,1996.

Kroll J, and Waltenberger J. The Vascular Endothelial Growth Factor Receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem 272: 32521-32527, 1997.

Kroll J, and Waltenberger J. VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun, 252: 743-746, 1998.

Kroll J, and Waltenberger, J. A novel function of VEGF receptor-2 (KDR): rapid release of nitric oxide in response to VEGF-A stimulation in endothelial cells. Biochem Biophys Res Commun, 265: 636-639, 1999.

Waltenberger J, Uecker A, Kroll J, Frank H, Mayr U, Bjorge J D, Fujita D, Gazit A, Hombach V, Levitzki A, and Bohmer FD. A dual inhibitor of platelet-derived growth factor beta-receptor and Src kinase activity potently interferes with motogenic and mitogenic responses to PDGF in vascular smooth muscle cells. A novel candidate for prevention of vascular remodeling. Circ Res, 85: 12-22, 1999.

Faehling M, Kroll J, Fohr KJ, Fellbrich G, Mayr U, Trischler G, and Waltenberger J. Essential role of calcium in vascular endothelial growth factor A-induced signaling: mechanism of the antiangiogenic effect of carboxyamidotriazole. Faseb J, 16: 1805-1807, 2002.

Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Shibuya M, Collen D, Conway EM, and Carmeliet P. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med, 9: 936-943, 2003.

Kroll J, Cobo P, and Sato TN. Versatile inducible activation system of Akt/PKB signaling pathway in mice. Genesis, 35: 160-163, 2003.

Kroll J*, Shi X*, Caprioli A*, Liu HH*, Waskow C, Lin KM, Miyazaki T, Rodewald HR, and Sato TN. The BTB-kelch Protein KLHL6 Is Involved in B-Lymphocyte Antigen Receptor Signaling and Germinal Center Formation. Mol Cell Biol, 25: 8531-8540, 2005.

*equal contribution

Nacak TG, Leptien K, Fellner D, Augustin HG, and Kroll J. The BTB-kelch protein LZTR-1 is a novel Golgi protein and is degraded upon induction of apoptosis. J Biol Chem 281: 5065-5071, 2006.

Krneta* J, Kroll J*, Alves A*, Prahst C, Sananbenesi F, Dullin F, Kimmina S, Phillips DJ, Augustin HG. Dissociation between angiogenesis and tumorigenesis in Activin and Follistatin overexpressing R30C tumors. Cancer Res 66: 5686-5695, 2006.

*equal contribution

Shraga-Heled N, Kessler O, Prahst C, Kroll J, Augustin HG, Neufeld G. Neuropilin-1 and Neuropilin-2 enhances VEGF₁₂₁ stimulated signal transduction by the VEGFR-2 receptor. Faseb J 21: 915-926, 2007.

Epting D, Vorwerk S, Hageman A, Meyer D. Expression of rasgef1b in zebrafish. Gene Expression Patterns 7: 389–395, 2007.

Nacak TG*, Alajati A*, Leptien K, Fulda C, Weber H, Miki T, Czepluch FS, Waltenberger J, Wieland T, Augustin HG, and Kroll J. The BTB-kelch protein KLEIP controls endothelial migration and sprouting angiogenesis. Circ Res 2007 100: 1155-63, 2007.

Klein D, Demory A, Peyre F, Kroll J, Augustin H G, Helfrich W, Kzhyshkowska J, Schledzewski K, Arnold B, and Goerdt S. Wnt2 acts as a cell type-specific, autocrinegrowth factor in rat hepatic sinusoidal endothelial cells cross-stimulating the VEGF pathway. Hepatology 47: 1018-1031, 2008.

Kroll J*, Epting D*, Kern K, Dietz CT, Feng Y, Hammes HP, Wieland T, and Augustin HG. Inhibition of Rho-dependent kinases ROCK I/II activates VEGF-driven retinal neovascularisation and sprouting angiogenesis. Am J Physiol Heart Circ Physiol , 296: H893-H899, 2009.

Klein D, Demory A, Peyre F, Kroll J, Géraud C, Ohnesorge N, Schledzewski K, Arnold B, and Goerdt S. Wnt2 acts as an angiogenic growth factor for non-sinusoidal endothelial cells and inhibits expression of stanniocalcin-1. Angiogenesis, 2009.

Epting D*, Wendik B*, Bennewitz K, Dietz CT, Driever W, and Kroll J. The Rac1 Regulator ELMO1 Controls Vascular Morphogenesis in Zebrafish. Circ Res.,106: 2010.

*equal contribution

- Reviews -

Taubert H, Wurl P, Meye A, Bache M, Kroll J, Lautenschlager C, Thamm B, Holzhausen HJ, Hinze R, Schmidt H, Berger D, and Rath FW. Frequency, distribution and prognostic relevance of p53 mutations in soft tissue sarcomas. Verh Dtsch Ges Pathol, 82: 340-344, 1998.

Kroll J. and Waltenberger J. Regulation of the endothelial function and angiogenesis by vascular endothelial growth factor-A (VEGF-A). Z Kardiol, 89: 206-218, 2000.

Funding

Deutsche Forschungsgemeinschaft