SFB 834:  Endothelial Signalling and Vascular Repair

• Subject Area: Medicine ; Biology
• Term: from 2010 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 75732319

• Final Report Year: 2022

Final Report Abstract

Diseases of the heart and circulatory system are the most frequent cause of death in Europe (45% of all deaths). Despite the fact that better measures have been developed to decrease and/or manage risk factors, such as hypercholesterolemia and hypertension, coronary artery disease and heart failure are the leading causes of death. Part of the problem is the increased incidence of diabetes and obesity as well as the increasing age of the general population, both of which are positively correlated with cardiovascular disease development. In addition, since most patients now survive a primary cardiovascular event, the proportion of chronic cardiovascular diseases, in particular heart failure is increasing. Endothelial activation or “dysfunction” is generally accepted to be one of the earliest measurable changes to take place within vessels during disease development and there is a well-documented relationship between attenuated endothelial function and poor patient prognosis. Our Collaborative Research Centre (CRC) therefore set out to identify molecular mechanisms and cellular mediators that determine endothelial cell function and repair in a series of translational basic science and clinical projects. The overall long-term goal being the development of new therapeutic concepts and their eventual transfer to the clinic. The main focus of the CRC in the first funding period was on establishing links between specific molecules and endothelial cell function as well as on the impact of different vascular niches and circulating cells for vascular repair. In the second finding period, the CRC picked up on the early reports of the importance of epigenetic regulation and the regulatory role played by microRNAs and long-non coding RNAs in vascular disease and integrated these aspects into basic and translational research projects. The final funding period continued its focus on epigenetic control but also made significant progress in addressing mechanisms underlying the metabolic programing/reprogramming of endothelial cells, endothelial cell diversity and plasticity as well as clonal haematopoiesis of indeterminate potential and the mechanisms determining vascular stability and mural cell coverage. One characteristic of the CRC, throughout all of the funding periods, was the enthusiastic application of state of the art methodologies and the recognition of novel trends from other research areas. This open mindset together with the close collaborative spirit resulted in the widespread use of next generation sequencing as well as proteomic and metabolomics approaches. One consequence was the parallel development of bioinformatics expertise in Frankfurt that benefited the majority of the individual projects.

Publications

• Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature, 473(7346), 234-238.
  Guarani, Virginia; Deflorian, Gianluca; Franco, Claudio A.; Krüger, Marcus; Phng, Li-Kun; Bentley, Katie; Toussaint, Louise; Dequiedt, Franck; Mostoslavsky, Raul; Schmidt, Mirko H. H.; Zimmermann, Barbara; Brandes, Ralf P.; Mione, Marina; Westphal, Christoph H.; Braun, Thomas; Zeiher, Andreas M.; Gerhardt, Holger; Dimmeler, Stefanie & Potente, Michael
  
• Nox4 Is a Protective Reactive Oxygen Species Generating Vascular NADPH Oxidase. Circulation Research, 110(9), 1217-1225.
  Schröder, Katrin; Zhang, Min; Benkhoff, Sebastian; Mieth, Anja; Pliquett, Rainer; Kosowski, Judith; Kruse, Christoph; Luedike, Peter; Michaelis, U. Ruth; Weissmann, Norbert; Dimmeler, Stefanie; Shah, Ajay M. & Brandes, Ralf P.
  
• AMP-Activated Protein Kinase Regulates Endothelial Cell Angiotensin-Converting Enzyme Expression via p53 and the Post-Transcriptional Regulation of microRNA-143/145. Circulation Research, 112(8), 1150-1158.
  Kohlstedt, Karin; Trouvain, Caroline; Boettger, Thomas; Shi, Lei; Fisslthaler, Beate & Fleming, Ingrid
  
• MicroRNA-34a regulates cardiac ageing and function. Nature, 495(7439), 107-110.
  Boon, Reinier A.; Iekushi, Kazuma; Lechner, Stefanie; Seeger, Timon; Fischer, Ariane; Heydt, Susanne; Kaluza, David; Tréguer, Karine; Carmona, Guillaume; Bonauer, Angelika; Horrevoets, Anton J. G.; Didier, Nathalie; Girmatsion, Zenawit; Biliczki, Peter; Ehrlich, Joachim R.; Katus, Hugo A.; Müller, Oliver J.; Potente, Michael; Zeiher, Andreas M.; ... & Dimmeler, Stefanie
  
• FLRT Structure: Balancing Repulsion and Cell Adhesion in Cortical and Vascular Development. Neuron, 84(2), 370-385.
  Seiradake, Elena; del Toro, Daniel; Nagel, Daniel; Cop, Florian; Härtl, Ricarda; Ruff, Tobias; Seyit-Bremer, Gönül; Harlos, Karl; Border, Ellen Clare; Acker-Palmer, Amparo; Jones, E. Yvonne & Klein, Rüdiger
  
• Long Noncoding RNA MALAT1 Regulates Endothelial Cell Function and Vessel Growth. Circulation Research, 114(9), 1389-1397.
  Michalik, Katharina M.; You, Xintian; Manavski, Yosif; Doddaballapur, Anuradha; Zörnig, Martin; Braun, Thomas; John, David; Ponomareva, Yuliya; Chen, Wei; Uchida, Shizuka; Boon, Reinier A. & Dimmeler, Stefanie
  
• STAT5-regulated microRNA-193b controls haematopoietic stem and progenitor cell expansion by modulating cytokine receptor signalling. Nature Communications, 6(1).
  Haetscher, Nadine; Feuermann, Yonatan; Wingert, Susanne; Rehage, Maike; Thalheimer, Frederic B.; Weiser, Christian; Bohnenberger, Hanibal; Jung, Klaus; Schroeder, Timm; Serve, Hubert; Oellerich, Thomas; Hennighausen, Lothar & Rieger, Michael A.
  
• The NADPH oxidase Nox4 has anti-atherosclerotic functions. European Heart Journal, 36(48), 3447-3456.
  Schürmann, Christoph; Rezende, Flavia; Kruse, Christoph; Yasar, Yakub; Löwe, Oliver; Fork, Christian; van de Sluis, Bart; Bremer, Rolf; Weissmann, Norbert; Shah, Ajay M.; Jo, Hanjoong; Brandes, Ralf P. & Schröder, Katrin
  
• Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release. Journal of Clinical Investigation, 126(12), 4527-4536.
  Wang, ShengPeng; Chennupati, Ramesh; Kaur, Harmandeep; Iring, Andras; Wettschureck, Nina & Offermanns, Stefan
  
• FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature, 529(7585), 216-220.
  Wilhelm, Kerstin; Happel, Katharina; Eelen, Guy; Schoors, Sandra; Oellerich, Mark F.; Lim, Radiance; Zimmermann, Barbara; Aspalter, Irene M.; Franco, Claudio A.; Boettger, Thomas; Braun, Thomas; Fruttiger, Marcus; Rajewsky, Klaus; Keller, Charles; Brüning, Jens C.; Gerhardt, Holger; Carmeliet, Peter & Potente, Michael
  
• Long Noncoding RNA Meg3 Controls Endothelial Cell Aging and Function. Journal of the American College of Cardiology, 68(23), 2589-2591.
  Boon, Reinier A.; Hofmann, Patrick; Michalik, Katharina M.; Lozano-Vidal, Noelia; Berghäuser, Denise; Fischer, Ariane; Knau, Andrea; Jaé, Nicolas; Schürmann, Christoph & Dimmeler, Stefanie
  
• Unchanged NADPH Oxidase Activity in Nox1-Nox2-Nox4 Triple Knockout Mice: What Do NADPH-Stimulated Chemiluminescence Assays Really Detect?. Antioxidants & Redox Signaling, 24(7), 392-399.
  Rezende, Flávia; Löwe, Oliver; Helfinger, Valeska; Prior, Kim-Kristin; Walter, Maria; Zukunft, Sven; Fleming, Ingrid; Weissmann, Norbert; Brandes, Ralf P. & Schröder, Katrin
  
• AMP-Activated Protein Kinase α2 in Neutrophils Regulates Vascular Repair via Hypoxia-Inducible Factor-1α and a Network of Proteins Affecting Metabolism and Apoptosis. Circulation Research, 120(1), 99-109.
  Abdel Malik, Randa; Zippel, Nina; Frömel, Timo; Heidler, Juliana; Zukunft, Sven; Walzog, Barbara; Ansari, Nariman; Pampaloni, Francesco; Wingert, Susanne; Rieger, Michael A.; Wittig, Ilka; Fisslthaler, Beate & Fleming, Ingrid
  
• Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy. Nature, 552(7684), 248-252.
  Hu, Jiong; Dziumbla, Sarah; Lin, Jihong; Bibli, Sofia-Iris; Zukunft, Sven; de Mos, Julian; Awwad, Khader; Frömel, Timo; Jungmann, Andreas; Devraj, Kavi; Cheng, Zhixing; Wang, Liya; Fauser, Sascha; Eberhart, Charles G.; Sodhi, Akrit; Hammock, Bruce D.; Liebner, Stefan; Müller, Oliver J.; Glaubitz, Clemens; ... & Fleming, Ingrid
  
• Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system. Science, 361(6404).
  Segarra, Marta; Aburto, Maria R.; Cop, Florian; Llaó-Cid, Cecília; Härtl, Ricarda; Damm, Miriam; Bethani, Ioanna; Parrilla, Marta; Husainie, Dewi; Schänzer, Anne; Schlierbach, Hannah; Acker, Till; Mohr, Laura; Torres-Masjoan, Laia; Ritter, Mathias & Acker-Palmer, Amparo
  
• Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells. Nature Communications, 9(1).
  Hitzel, Juliane; Lee, Eunjee; Zhang, Yi; Bibli, Sofia Iris; Li, Xiaogang; Zukunft, Sven; Pflüger, Beatrice; Hu, Jiong; Schürmann, Christoph; Vasconez, Andrea Estefania; Oo, James A.; Kratzer, Adelheid; Kumar, Sandeep; Rezende, Flávia; Josipovic, Ivana; Thomas, Dominique; Giral, Hector; Schreiber, Yannick; Geisslinger, Gerd; ... & Brandes, Ralf P.
  
• Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation. Journal of Experimental Medicine, 215(10), 2655-2672.
  Albarrán-Juárez, Julián; Iring, Andras; Wang, ShengPeng; Joseph, Sayali; Grimm, Myriam; Strilic, Boris; Wettschureck, Nina; Althoff, Till F. & Offermanns, Stefan
  
• Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure. JAMA Cardiology, 4(1), 25.
  Dorsheimer, Lena; Assmus, Birgit; Rasper, Tina; Ortmann, Christina A.; Ecke, Andreas; Abou-El-Ardat, Khalil; Schmid, Tobias; Brüne, Bernhard; Wagner, Sebastian; Serve, Hubert; Hoffmann, Jedrzej; Seeger, Florian; Dimmeler, Stefanie; Zeiher, Andreas M. & Rieger, Michael A.
  
• Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. European Heart Journal, 41(8), 933-939.
  Mas-Peiro, Silvia; Hoffmann, Jedrzej; Fichtlscherer, Stephan; Dorsheimer, Lena; Rieger, Michael A; Dimmeler, Stefanie; Vasa-Nicotera, Mariuca & Zeiher, Andreas M
  
• Deubiquitinase USP10 regulates Notch signaling in the endothelium. Science, 364(6436), 188-193.
  Lim, R.; Sugino, T.; Nolte, H.; Andrade, J.; Zimmermann, B.; Shi, C.; Doddaballapur, A.; Ong, Y. T.; Wilhelm, K.; Fasse, J. W. D.; Ernst, A.; Kaulich, M.; Husnjak, K.; Boettger, T.; Guenther, S.; Braun, T.; Krüger, M.; Benedito, R.; Dikic, I. & Potente, M.
  
• Hematopoietic Deficiency of the Long Noncoding RNA MALAT1 Promotes Atherosclerosis and Plaque Inflammation. Circulation, 139(10), 1320-1334.
  Cremer, Sebastian; Michalik, Katharina M.; Fischer, Ariane; Pfisterer, Larissa; Jaé, Nicolas; Winter, Carla; Boon, Reinier A.; Muhly-Reinholz, Marion; John, David; Uchida, Shizuka; Weber, Christian; Poller, Wolfgang; Günther, Stefan; Braun, Thomas; Li, Daniel Y.; Maegdefessel, Lars; Perisic Matic, Ljubica; Hedin, Ulf; Soehnlein, Oliver; ... & Dimmeler, Stefanie
  
• Nitric oxide maintains endothelial redox homeostasis through PKM 2 inhibition. The EMBO Journal, 38(17).
  Siragusa, Mauro; Thöle, Janina; Bibli, Sofia‐Iris; Luck, Bert; Loot, Annemarieke E; de Silva, Kevin; Wittig, Ilka; Heidler, Juliana; Stingl, Heike; Randriamboavonjy, Voahanginirina; Kohlstedt, Karin; Brüne, Bernhard; Weigert, Andreas; Fisslthaler, Beate & Fleming, Ingrid
  
• Shear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure. Journal of Clinical Investigation, 129(7), 2775-2791.
  Iring, Andras; Jin, Young-June; Albarrán-Juárez, Julián; Siragusa, Mauro; Wang, ShengPeng; Dancs, Péter T.; Nakayama, Akiko; Tonack, Sarah; Chen, Min; Künne, Carsten; Sokol, Anna M.; Günther, Stefan; Martínez, Alfredo; Fleming, Ingrid; Wettschureck, Nina; Graumann, Johannes; Weinstein, Lee S. & Offermanns, Stefan
  
• Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity. Journal of Clinical Investigation, 129(12), 5204-5218.
  Hu, Jiong; Bibli, Sofia-Iris; Wittig, Janina; Zukunft, Sven; Lin, Jihong; Hammes, Hans-Peter; Popp, Rüdiger & Fleming, Ingrid
  
• Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction. Nature Communications, 11(1).
  Trembinski, D. Julia; Bink, Diewertje I.; Theodorou, Kosta; Sommer, Janina; Fischer, Ariane; van Bergen, Anke; Kuo, Chao-Chung; Costa, Ivan G.; Schürmann, Christoph; Leisegang, Matthias S.; Brandes, Ralf P.; Alekseeva, Tijna; Brill, Boris; Wietelmann, Astrid; Johnson, Christopher N.; Spring-Connell, Alexander; Kaulich, Manuel; Werfel, Stanislas; Engelhardt, Stefan; ... & Boon, Reinier A.
  
• Apelin signaling drives vascular endothelial cells toward a pro-angiogenic state. eLife, 9(2020, 9, 21).
  Helker, Christian SM; Eberlein, Jean; Wilhelm, Kerstin; Sugino, Toshiya; Malchow, Julian; Schuermann, Annika; Baumeister, Stefan; Kwon, Hyouk-Bum; Maischein, Hans-Martin; Potente, Michael; Herzog, Wiebke & Stainier, Didier YR
  
• Arterialization requires the timely suppression of cell growth. Nature, 589(7842), 437-441.
  Luo, Wen; Garcia-Gonzalez, Irene; Fernández-Chacón, Macarena; Casquero-Garcia, Verónica; Sanchez-Muñoz, Maria S.; Mühleder, Severin; Garcia-Ortega, Lourdes; Andrade, Jorge; Potente, Michael & Benedito, Rui
  
• Clonal haematopoiesis in chronic ischaemic heart failure: prognostic role of clone size for DNMT3A- and TET2-driver gene mutations. European Heart Journal, 42(3), 257-265.
  Assmus, Birgit; Cremer, Sebastian; Kirschbaum, Klara; Culmann, David; Kiefer, Katharina; Dorsheimer, Lena; Rasper, Tina; Abou-El-Ardat, Khalil; Herrmann, Eva; Berkowitsch, Alexander; Hoffmann, Jedrzej; Seeger, Florian; Mas-Peiro, Silvia; Rieger, Michael A; Dimmeler, Stefanie & Zeiher, Andreas M
  
• Single-cell RNA-sequencing reveals profound changes in circulating immune cells in patients with heart failure. Cardiovascular Research, 117(2), 484-494.
  Abplanalp, Wesley T; John, David; Cremer, Sebastian; Assmus, Birgit; Dorsheimer, Lena; Hoffmann, Jedrzej; Becker-Pergola, Graziella; Rieger, Michael A; Zeiher, Andreas M; Vasa-Nicotera, Mariuca & Dimmeler, Stefanie
  
• The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition. Proceedings of the National Academy of Sciences, 117(8), 4180-4187.
  Glaser, Simone F.; Heumüller, Andreas W.; Tombor, Lukas; Hofmann, Patrick; Muhly-Reinholz, Marion; Fischer, Ariane; Günther, Stefan; Kokot, Karoline E.; Okada, Hitoshi; Hassel, David; Kumar, Sandeep; Jo, Hanjoong; Boon, Reinier A.; Abplanalp, Wesley; John, David; Boeckel, Jes-Niels & Dimmeler, Stefanie
  
• Clonal Hematopoiesis–Driver DNMT3A Mutations Alter Immune Cells in Heart Failure. Circulation Research, 128(2), 216-228.
  Abplanalp, Wesley Tyler; Cremer, Sebastian; John, David; Hoffmann, Jedrzej; Schuhmacher, Bianca; Merten, Maximillian; Rieger, Michael A.; Vasa-Nicotera, Mariuca; Zeiher, Andreas M. & Dimmeler, Stefanie
  
• Control of endothelial quiescence by FOXO-regulated metabolites. Nature Cell Biology, 23(4), 413-423.
  Andrade, Jorge; Shi, Chenyue; Costa, Ana S. H.; Choi, Jeongwoon; Kim, Jaeryung; Doddaballapur, Anuradha; Sugino, Toshiya; Ong, Yu Ting; Castro, Marco; Zimmermann, Barbara; Kaulich, Manuel; Guenther, Stefan; Wilhelm, Kerstin; Kubota, Yoshiaki; Braun, Thomas; Koh, Gou Young; Grosso, Ana Rita; Frezza, Christian & Potente, Michael
  
• GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis. Proceedings of the National Academy of Sciences, 118(17).
  Le Mercier, Alan; Bonnavion, Remy; Yu, Weijia; Alnouri, Mohamad Wessam; Ramas, Sophie; Zhang, Yang; Jäger, Yannick; Roquid, Kenneth Anthony; Jeong, Hyun-Woo; Sivaraj, Kishor Kumar; Cho, Haaglim; Chen, Xinyi; Strilic, Boris; Sijmonsma, Tjeerd; Adams, Ralf; Schroeder, Timm; Rieger, Michael A. & Offermanns, Stefan
  
• Neurovascular crosstalk coordinates the central nervous system development. Current Opinion in Neurobiology, 69(2021, 8), 202-213.
  Peguera, Blanca; Segarra, Marta & Acker-Palmer, Amparo
  
• Post-myocardial infarction heart failure dysregulates the bone vascular niche. Nature Communications, 12(1).
  Hoffmann, Jedrzej; Luxán, Guillermo; Abplanalp, Wesley Tyler; Glaser, Simone-Franziska; Rasper, Tina; Fischer, Ariane; Muhly-Reinholz, Marion; Potente, Michael; Assmus, Birgit; John, David; Zeiher, Andreas Michael & Dimmeler, Stefanie
  
• Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation. Journal of Clinical Investigation, 131(21).
  Jin, Young-June; Chennupati, Ramesh; Li, Rui; Liang, Guozheng; Wang, ShengPeng; Iring, András; Graumann, Johannes; Wettschureck, Nina & Offermanns, Stefan
  
• Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction. Nature Communications, 12(1).
  Tombor, Lukas S.; John, David; Glaser, Simone F.; Luxán, Guillermo; Forte, Elvira; Furtado, Milena; Rosenthal, Nadia; Baumgarten, Nina; Schulz, Marcel H.; Wittig, Janina; Rogg, Eva-Maria; Manavski, Yosif; Fischer, Ariane; Muhly-Reinholz, Marion; Klee, Kathrin; Looso, Mario; Selignow, Carmen; Acker, Till; Bibli, Sofia-Iris; ... & Dimmeler, Stefanie
  
• A YAP/TAZ-TEAD signalling module links endothelial nutrient acquisition to angiogenic growth. Nature Metabolism, 4(6), 672-682.
  Ong, Yu Ting; Andrade, Jorge; Armbruster, Max; Shi, Chenyue; Castro, Marco; Costa, Ana S. H.; Sugino, Toshiya; Eelen, Guy; Zimmermann, Barbara; Wilhelm, Kerstin; Lim, Joseph; Watanabe, Shuichi; Guenther, Stefan; Schneider, Andre; Zanconato, Francesca; Kaulich, Manuel; Pan, Duojia; Braun, Thomas; Gerhardt, Holger; ... & Potente, Michael
  
• Apelin signaling dependent endocardial protrusions promote cardiac trabeculation in zebrafish. eLife, 11(2022, 2, 28).
  Qi, Jialing; Rittershaus, Annegret; Priya, Rashmi; Mansingh, Shivani; Stainier, Didier YR & Helker, Christian SM
  
• Nox4 promotes endothelial differentiation through chromatin remodeling. Redox Biology, 55(2022, 9), 102381.
  Hahner, F.; Moll, F.; Warwick, T.; Hebchen, D.M.; Buchmann, G.K.; Epah, J.; Abplanalp, W.; Schader, T.; Günther, S.; Gilsbach, R.; Brandes, R.P. & Schröder, K.