SFB 688:  Mechanisms and Imaging of Cell-Cell-Interactions in the Cardiovascular System

• Subject Area: Medicine ; Biology
• Term: from 2006 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 14085162

• Final Report Year: 2018

Final Report Abstract

The cardiovascular system comprises a multitude of cell populations that interact in spatio- and temporal tightly controlled manner to ensure not only the supply of organs with oxygen and nutrients, but also to safeguard inflammation, healing and remodelling processes. The physiological interaction between platelets, inflammatory cells, endothelial cells and other vascular or neighbouring cells is essential for normal haemostasis and the control of vascular barrier function. Disturbances of these cell-cell interactions under pathological conditions can lead to thrombosis, atherosclerosis and inflammation and precipitate cardio- and cerebrovascular diseases, such as myocardial infarction or stroke. The goal of the SFB 688 was therefore to analyse these cell-cell interactions in a translational and interdisciplinary approach by using state of the art imaging techniques, molecular biological methods, and relevant disease models in order to identify novel targets for pharmacological intervention and to develop novel experimental-therapeutical strategies for the (pre)clinical validation of these targets. Research in the SFB 688 focussed on four major areas: (1) Mechanisms underlying intravascular thrombus formation and ischemic/inflammatory processes; (2) Regulation of endothelial barrier function; (3) Cardiovascular signal transduction and regulatory processes and (4) Imaging of cardiovascular cell-cell interactions. A major methodical strength of the SFB 688 was the generation of new transgenic mouse models and their analysis in different disease models (project area A). A second focus comprised the development and application of novel imaging techniques for the dynamic visualization of these experimental disease processes in mice (project area B). We were not only able to elucidate fundamental disease mechanisms, but we also identified and (pre)clinically validated a number of novel potential pharmacological targets, some of which have in the meantime entered clinical trials. Importantly, the work of the SFB 688 formed the basis for a change of paradigm in a central area of the field of cardiovascular research: We were the first to describe the nowadays widely recognized process “thrombo-inflammation” as a fundamental pathomechanism underlying ischemic/inflammatory pathologies and developed first strategies to therapeutically control these processes in experimental disease models. Together, these and further achievements have enabled a better understanding of cardiovascular cell-cell interactions and provided the basis for future research in the field of cardio- and cerebrovascular diseases like for example the new CRC/TR 240 “Platelets” (Würzburg/Tübingen) that commences its work in July 2018.

Publications

• (2006). Molecular transport through channels and pores: effects of in-channel interactions and blocking. Proc Natl Acad Sci U S A. 103:11446-51
  Bauer WR, Nadler W
  (See online at https://doi.org/10.1073/pnas.0601769103)
• (2006). Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med 203, 513-608
  Kleinschnitz C, Stoll G, Bendszus M, Schuh K, Pauer HU, Burfeind P, Renné C, Gailani D, Nieswandt B, Renné T
  (See online at https://doi.org/10.1084/jem.20052458)
• (2007). An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice. J Clin Invest 117, 3540-50
  Grosse J, Braun A, Varga-Szabo D, Beyersdorf N, Schneider B, Zeitlmann L, Hanke P, Schropp P, Mühlstedt S, Zorn C, Huber M, Schmittwolf C, Jagla W, Yu P, Kerkau T, Schulze H, Nehls M, Nieswandt B
  (See online at https://doi.org/10.1172/jci32312)
• (2007). Scaling laws for transverse relaxation times. J Magn Reson 184:169-75
  Ziener CH, Kampf T, Melkus G, Jakob PM, Bauer WR
  (See online at https://doi.org/10.1016/j.jmr.2006.09.018)
• (2007). Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation 115, 2323-30
  Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G
  (See online at https://doi.org/10.1161/circulationaha.107.691279)
• (2008) The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J Exp Med 205, 1583-91
  Varga-Szabo D, Braun A, Kleinschnitz C, Bender M, Pleines I, Pham M, Renné T, Stoll G, Nieswandt B
  (See online at https://doi.org/10.1084/jem.20080302)
• (2008). Cytoskeleton assembly at endothelial cell-cell contacts is regulated by alphaII- spectrin-VASP complexes. J Cell Biol 180, 205-19
  Benz PM, Blume C, Moebius J, Oschatz C, Schuh K, Sickmann A, Walter U, Feller SM, Renné T
  (See online at https://doi.org/10.1083/jcb.200709181)
• (2008). Platelet protein interactions: map, signaling components, and phosphorylation groundstate. Arterioscler Thromb Vasc Biol 28, 1326-31
  Dittrich M, Birschmann I, Mietner S, Sickmann A, Walter U, Dandekar T
  (See online at https://doi.org/10.1161/atvbaha.107.161000)
• (2009). A new type of ERK1/2 autophosphorylation causes cardiac hypertrophy. Nat Med 15:75-83
  Lorenz K, Schmitt JP, Schmitteckert EM, Lohse MJ
  (See online at https://doi.org/10.1038/nm.1893)
• (2009). Lipopolysaccharide-induced endothelial barrier breakdown is cyclic adenosine monophosphate dependent in vivo and in vitro. Crit Care Med 37:1735-43
  Schlegel N, Baumer Y, Drenckhahn D, Waschke J
  (See online at https://doi.org/10.1097/ccm.0b013e31819deb6a)
• (2009). Platelet membrane proteomics: A novel repository for functional research. Blood 114, e10-9
  Lewandrowski U, Wortelkamp S, Lohrig K, Zahedi RP, Wolters D, Walter U, Sickmann A
  (See online at https://doi.org/10.1182/blood-2009-02-203828)
• (2009). The natriuretic peptide / guanylyl cyclase-A system functions as a stress-responsive regulator of angiogenesis in mice. J Clin Invest 119, 2019-30
  Kuhn M, Völker K, Schwarz K, Carbajo-Loyola J, Flögel U, Jacoby C, Stypmann J, van Eickels M, Gambaryan S, Werner M, Hartmann M, Wieland T, Schrader J, Baba HA
  (See online at https://doi.org/10.1172/jci37430)
• (2010). Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 115:3835-42
  Kleinschnitz C, Schwab N, Kraft P, Hagedorn I, Dreykluft A, Schwarz T, Austinat M, Nieswandt B, Wiendl H, Stoll G
  (See online at https://doi.org/10.1182/blood-2009-10-249078)
• (2010). Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation 121, 1510-7
  Hagedorn I, Schmidbauer S, Pleines I, Kleinschnitz C, Kronthaler U, Stoll G, Dickneite G, Nieswandt B
  (See online at https://doi.org/10.1161/circulationaha.109.924761)
• (2010). Impaired alpha(IIb)beta(3) integrin activation and shear-dependent thrombus formation in mice lacking phospholipase D1. Sci Signal 3:ra1
  Elvers M, Stegner D, Hagedorn I, Kleinschnitz C, Braun A, Kuijpers ME, Boesl M, Chen Q, Heemskerk JW, Stoll G, Frohman MA, Nieswandt B
  (See online at https://doi.org/10.1126/scisignal.2000551)
• (2010). Outcome of experimental stroke in C57Bl/6 and Sv/129 mice assessed by multimodal ultra-high field MRI. Exp Transl Stroke Med 2, 6
  Pham M, Helluy X, Braeuninger S, Jakob P, Stoll G, Kleinschnitz C, Bendszus M
  (See online at https://doi.org/10.1186/2040-7378-2-6)
• (2011). A cardiac pathway of cyclic GMP-independent signaling of guanylyl cyclase A, the receptor for atrial natriuretic peptide. Proc Natl Acad Sci U S A 108, 18500-5
  Klaiber M, Dankworth B, Kruse M, Hartmann M, Nikolaev VO, Yang RB, Völker K, Gaßner B, Oberwinkler H, Feil R, Freichel M, Groschner K, Skryabin BV, Frantz S, Birnbaumer L, Pongs O, Kuhn M
  (See online at https://doi.org/10.1073/pnas.1103300108)
• (2011). CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice. J Clin Invest 121, 2898-2910
  Weber C, Meiler S, Döring Y, Koch M, Drechsler M, Megens RT, Rowinska Z, Bidzhekov K, Fecher C, Ribechini E, van Zandvoort MA, Binder CJ, Jelinek I, Hristov M, Boon L, Jung S, Korn T, Lutz MB, Förster I, Zenke M, Hieronymus T, Junt T, Zernecke A
  (See online at https://doi.org/10.1172/jci44925)
• (2012). Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation 125, 1652-63
  Hofmann U, Beyersdorf N, Weirather J, Podolskaya A, Bauersachs J, Ertl G, Kerkau T, Frantz S
  (See online at https://doi.org/10.1161/circulationaha.111.044164)
• (2012). Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain-barrier damage and inflammation. Blood 120, 4082-92
  Langhauser F, Göb E, Kraft P, Geis C, Schmitt J, Brede M, Göbel K, Helluy X, Pham M, Bendszus M, Jakob P, Stoll G, Meuth SG, Nieswandt B, McKrae KR, Kleinschnitz C
  (See online at https://doi.org/10.1182/blood-2012-06-440057)
• (2012). PlateletWeb: A systems biological analysis of signaling networks in human platelets. Blood 119, e22-34
  Boyanova D, Nilla S, Birschmann I, Dandekar T, Dittrich M
  (See online at https://doi.org/10.1182/blood-2011-10-387308)
• (2012). Target gene analysis by microarrays and chromatin immunoprecipitation identifies HEY proteins as highly redundant bHLH repressors. PLoS Genet 8, e1002728
  Heisig J, Weber D, Englberger E, Winkler A, Kneitz S, Sung WK, Wolf E, Eilers M, Wei CL, Gessler M
  (See online at https://doi.org/10.1371/journal.pgen.1002728)
• (2013). Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet. 45:1044-9. Erratum in: Nat Genet 2013, 45:1409
  Bezzina CR, Barc J, Mizusawa Y, Remme CA, Gourraud JB, Simonet F, Verkerk AO, Schwartz PJ, Crotti L, Dagradi F, Guicheney P, Fressart V, Leenhardt A, Antzelevitch C, Bartkowiak S, Borggrefe M, Schimpf R, Schulze-Bahr E, Zumhagen S, Behr ER, Bastiaenen R, Tfelt-Hansen J, Olesen MS, Kääb S, Beckmann BM, Weeke P, Watanabe H, Endo N, Minamino T, Horie M, Ohno S, Hasegawa K, Makita N, Nogami A, Shimizu W, Aiba T, Froguel P, Balkau B, Lantieri O, Torchio M, Wiese C, Weber D, Wolswinkel R, Coronel R, Boukens BJ, Bézieau S, Charpentier E, Chatel S, Despres A, Gros F, Kyndt F, Lecointe S, Lindenbaum P, Portero V, Violleau J, Gessler M, Tan HL, Roden DM, Christoffels VM, Le Marec H, Wilde AA, Probst V, Schott JJ, Dina C, Redon R
  (See online at https://doi.org/10.1038/ng.2712)
• (2013). Gray platelet syndrome and thrombo-inflammation in Nbeal2-deficient mice. J Clin Invest 123, 3331-42
  Deppermann C, Cherpokova C, Nurden P, Schulz JN, Thielmann I, Kraft P, Vögtle T, Kleinschnitz C, Dütting S, Krohne G, Eming SA, Nurden AT, Eckes B, Stoll G, Stegner D, Nieswandt B
  (See online at https://doi.org/10.1172/jci69210)
• (2013). Interference with ERKThr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy. Proc Natl Acad Sci U S A 110, 7440-5
  Ruppert C, Deiss K, Herrmann S, Vidal M, Oezkur M, Gorski A, Weidemann F, Lohse MJ, Lorenz K
  (See online at https://doi.org/10.1073/pnas.1221999110)
• (2013). Only severe thrombocytopenia results in bleeding and defective thrombus formation in mice. Blood 121:4938-47
  Morowski M, Vögtle T, Kraft P, Kleinschnitz C, Stoll G, Nieswandt B
  (See online at https://doi.org/10.1182/blood-2012-10-461459)
• (2014). Targeting P-selectin by gallium-68-labeled fucoidan positron emission tomography for noninvasive characterization of vulnerable plaques: correlation with in vivo 17.6T MRI. Arterioscler Thromb Vasc Biol 34, 1661-1667
  Li X, Bauer WR, Israel I, Kreissl MC, Weirather J, Richter D, Bauer E, Herold V, Jakob P, Buck A, Frantz S, Samnick S
  (See online at https://doi.org/10.1161/atvbaha.114.303485)
• (2015). Cardiac RKIP causes a beneficial beta-adrenoceptor-dependent positive inotropy. Nat Med 21, 1298-306
  Schmid E, Neef S, Berlin C, Tomasovic A, Kahlert K, Nordbeck P, Deiss K, Denzinger S, Herrmann S, Wettwer E, Weidendorfer M, Becker D, Schäfer F, Wagner N, Ergün S, Schmitt JP, Katus HA, Weidemann F, Ravens U, Maack C, Hein L, Ertl G, Müller OJ, Maier LS, Lohse MJ, Lorenz K
  (See online at https://doi.org/10.1038/nm.3972)
• (2015). CD8+ T cells regulate monopoiesis and circulating Ly6C-high monocyte levels in atherosclerosis in mice. Circ Res 117:244-53
  Cochain C, Koch M, Chaudhari SM, Busch M, Pelisek J, Boon L, Zernecke A
  (See online at https://doi.org/10.1161/circresaha.117.304611)
• (2016). cAMP Signals in Drosophila motor neurons are confined to single synaptic boutons. Cell Rep 17, 1238-46
  Maiellaro I, Lohse MJ, Kittel RJ, Calebiro D
  (See online at https://doi.org/10.1016/j.celrep.2016.09.090)
• (2016). Chronophin is a glial tumor modifier involved in the regulation of glioblastoma growth and invasiveness. Oncogene 35, 3163-77
  Schulze M, Fedorchenko O, Sondergeld T, Knobbe-Thomsen C, Kraus S, Schwinn S, Beilhack A, Reifenberger G, Monoranu CM, Sirén AL, Jeanclos E, Gohla A
  (See online at https://doi.org/10.1038/onc.2015.376)
• (2016). Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg(2+) homeostasis and cytoskeletal architecture. Nat Commun 7, 11097
  Stritt S, Nurden P, Favier R, Favier M, Ferioli S, Gotru SK, van Eeuwijk JM, Schulze H, Nurden AT, Lambert MP, Turro E, Burger-Stritt S, Matsushita M, Mittermeier L, Ballerini P, Zierler S, Laffan MA, Chubanov V, Gudermann T, Nieswandt B, Braun A
  (See online at https://doi.org/10.1038/ncomms11097)
• (2016). Endothelial actions of ANP enhance myocardial inflammatory infiltration in the early phase after acute infarction. Circ Res 119, 237-248
  Chen W, Spitzl A, Mathes D, Nikolaev VO, Werner F, Weirather J, Špiranec K, Röck K, Fischer JW, Kämmerer U, Stegner D, Baba HA, Hofmann U, Frantz S, Kuhn M
  (See online at https://doi.org/10.1161/circresaha.115.307196)
• (2017). A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis. Nat Commun 8, 15838
  Dütting S, Gaits-Iacovoni F, Stegner D, Popp M, Antkowiak A, van Eeuwijk JMM, Nurden P, Stritt S, Heib T, Aurbach K, Angay O, Cherpokova D, Heinz N, Baig A, Gorelashvili M, Gerner F, Heinze KG, Ware J, Krohne G, Ruggeri Z, Nurden A, Schulze H, Modlich U, Pleines I, Brakebusch, Nieswandt B
  (See online at https://doi.org/10.1038/ncomms15838)
• (2017). Gene expression profiles of brain endothelial cells during embryonic development at bulk and single-cell levels. Sci Signal 10, eaag2476
  Hupe M, Li MX, Kneitz S, Davydova D, Yokota C, Kele-Olovsson J, Hot B, Stenman JM, Gessler M
  (See online at https://doi.org/10.1126/scisignal.aag2476)
• (2017). Oncostatin M induces RIG-I and MDA5 expression and enhances the double-stranded RNA response in fibroblasts. J Cell Mol Med 21, 3087-3099
  Hergovits S, Mais C, Haan C, Costa-Pereira AP, Hermanns HM
  (See online at https://doi.org/10.1111/jcmm.13221)
• (2017). Thrombopoiesis is spatially regulated by the bone marrow vasculature. Nat Commun 8, 127
  Stegner D, van Eeuwijk JMM, Angay O, Gorelashvili M, Semeniak D, Pinnecker J, Schmithausen P, Meyer I, Friedrich M, Dütting S, Brede C, Beilhack A, Schulze H, Nieswandt B, Heinze KG
  (See online at https://doi.org/10.1038/s41467-017-00201-7)
• (2018). Endothelial barrier function is differentially regulated by CEACAM1- mediated signaling. FASEB J 10, fj201800331R
  Ghavampour S, Kleefeldt F, Bömmel H, Volland J, Paus A, Horst A, Pfeiffer V, Hübner S, Wagner N, Rueckschloss U, Ergün S
  (See online at https://doi.org/10.1096/fj.201800331r)
• (2018). Endothelial C-type natriuretic peptide acts on pericytes to regulate microcirculatory flow and blood pressure. Circulation
  Špiranec K, Chen W, Werner F, Nikolaev VO, Naruke T, Koch F, Werner A, Eder-Negrin P, Diéguez- Hurtado R, Adams RH, Baba HA, Schmidt H, Schuh K, Skryabin BV, Movahedi K, Schweda F, Kuhn M
  (See online at https://doi.org/10.1161/circulationaha.117.033383)
• (2018). TRPM7 kinase controls calcium responses in arterial thrombosis and stroke in mice. Arterioscler Thromb Vasc Biol 38, 344-52
  Gotru SK, Chen W, Kraft P, Becker IC, Wolf K, Stritt S, Zierler S, Hermanns HM, Rao D, Perraud AL, Schmitz C, Zahedi RP, Noy PJ, Tomlinson MG, Dandekar T, Matsushita M, Chubanov V, Gudermann T, Stoll G, Nieswandt B, Braun A
  (See online at https://doi.org/10.1161/atvbaha.117.310391)