AG Fischer: Vascular Signaling

Blood vessels supply almost every cell in the human body with oxygen and nutrients. However, blood vessels are not simple, passive tubes enabling the transport of blood, but also instruct tissue regeneration, stem cell renewal and differentiation, as well as tumor progression. In addition, there is increasing evidence that signaling pathways in endothelial cells actively control the transport of nutrients, hormones, immune and cancer cells across the vessel wall. As such, the endothelium appears to act as a communication platform that integrates numerous signals from blood and parenchymal cells to actively maintain homeostasis.

Our research activities aim at studying signaling pathways that control blood vessel growth and angiocrine functions and its implications on organ function. We focus on cardiac and skeletal muscle as well as solid tumors. Our laboratory has identified Delta/Notch signaling in the endothelium as key player of angiogenesis, barrier control, metabolism and metastasis. We aim at understanding how endothelial cells orchestrate inflammation and tumor progression. Secondly, we aim at understanding the roles of endothelial cells as organ-specific sensors of plasma metabolites and how this alters the transcriptional landscape and the functions of the endothelium.

Fluorescence microscopy image of a tumor. Blood vessels are stained in green (endothelial cells) and red (mural cells), cell nuclei in blue.

Kontakt

Institutsdirektor

Prof. Dr. med. Andreas Fischer

Prof. Dr. med. Andreas Fischer

Kontaktinformationen

Key publications

Taylor J, Uhl L, Moll I, Safatul SH, Wiedmann L, Morgenstern J, Giaimo BD, Friedrich T, Alsina-Sanchis E, De Angelis Rigotti F, Mülfarth R, Kaltenbach S, Schenk D, Nickel F, Fleming T, Sprinzak D, Mogler C, Korff T, Billeter AT, Müller-Stich BP, Berriel Diaz M, Borggrefe T, Herzig S, Rohm M, Rodriguez-Vita J*, Fischer A*. Endothelial Notch1 signalling in white adipose tissue promotes cancer cachexia. Nature Cancer. 2023 in press.

Wiedmann L*, De Angelis Rigotti F*, Vaquero-Siguero  N, Donato  E, Espinet  E , Moll  I, Alsina-Sanchis E, Bohnenberger  H, Fernandez-Florido  E, Mülfarth  R, Vacca  M, Gerwing  J, Conradi  LC, Ströbel  P, Trumpp  A, Mogler  C, Fischer  A*, Rodriguez-Vita J*. HAPLN1 potentiates peritoneal metastasis in pancreatic cancer. Nat Commun. 14(1):2353; 2023.  *, equal contribution

De Angelis Rigotti F,* Wiedmann L*, Hubert MO, Vacca M, Hasan SS, Moll I, Carvajal S, Jiménez W, Starostecka M, Billeter AT, Müller-Stich B, Wolff G, Ekim-Üstünel B, Herzig S, Fandos-Ramo C, Krätzner R, Reich M, Keitel-Anselmino V, Heikenwälder M, Mogler C, Fischer A*, Rodriguez-Vita J*. Semaphorin 3C exacerbates liver fibrosis.mHepatology. Apr 15; 2023. *, equal contribution

Alsina-Sanchis E*, Mülfarth R*, Moll I, Böhn S, Wiedmann L, Jordana-Urriza L, Ziegelbauer T, Zimmer E, Taylor J, De Angelis Rigotti F, Stögbauer A, Giaimo BD, Cerwenka A, Borggrefe T, Fischer A*, Rodriguez-Vita J*. Endothelial RBPJ Is Essential for the Education of Tumor-Associated Macrophages. Cancer Res. 82(23):4414-4428. 2022.  *, equal contribution

Weis EM, Puchalska P, Nelson A, Taylor J, Moll I, Hasan SS, Dewenter M, Hagenmueller M, Fleming T, Poschet G, Hotz-Wagenblatt A, Backs J, Crawford P, Fischer A. Ketone body oxidation increases cardiac endothelial cell proliferation. EMBO Mol Med. 2022 14(4):e14753.

Hasan SS*, Jabs M*, Taylor J, Wiedmann L, Leibing T, Nordström V, Federico G, Roma LP, Carlein C, Wolff G, Ekim-Üstünel B, Brune M, Moll I, Tetzlaff F, Gröne H-J, Fleming T, Géraud C, Herzig S, Nawroth PP, Fischer A: Endothelial Notch signaling controls insulin transport in muscle. EMBO Mol Med, 12(4):e09271., 2020.

Jabs M, Rose AJ, Lehmann LH, Taylor J, Moll I, Sijmonsma TP, Herberich SE, Sauer SW, Poschet G, Federico G, Mogler C, Weis EM, Augustin HG, Yan M, Gretz N, Schmid RM, Adams RH, Gröne HJ, Hell R, Okun JG, Backs J, Nawroth PP, Herzig S, Fischer A. (2018) Inhibition of endothelial Notch signaling impairs fatty acid transport and leads to metabolic and vascular remodeling of the adult heart. Circulation. Jun 12;137(24):2592-2608.

Tetzlaff F, Adam MG, Feldner A, Moll I, Menuchin A, Rodriguez-Vita J, Sprinzak D, Fischer A. (2018) MPDZ promotes DLL4-induced Notch signaling during angiogenesis. eLife. Apr 5;7. pii: e32860.

Feldner A, Adam MG, Tetzlaff F, Moll I, Komljenovic D, Sahm F, Bäuerle T, Ishikawa H, Schroten H, Korff T, Hofmann I, Wolburg H, von Deimling A, Fischer A. Loss of Mpdz impairs ependymal cell integrity leading to perinatal-onset hydrocephalus in mice. EMBO Mol Med. Jul;9(7):890-905., 2017

Wieland E*, Rodriguez-Vita J*, Liebler SS, Mogler C, Moll I, Herberich SE, Espinet E, Herpel E, Menuchin A, Chang-Claude J, Hoffmeister M, Gebhardt C, Brenner H, Trumpp A, Siebel CW, Hecker M, Utikal J, Sprinzak D, Fischer A: Endothelial Notch1 activity facilitates metastasis. Cancer Cell, 3: 355-367, 2017. 

Adam MG, Berger C, Feldner A, Yang W-J, Wüstehube-Lausch J, Herberich SE, Pinder M, Gesierich S, Hammes H-P, Augustin HG, Fischer A (2013) Synaptojanin-2 binding protein stabilizes the Notch ligands DLL1 and DLL4 and inhibits sprouting angiogenesis. Circ Res. 113: 1206-1218.

Wüstehube J, Bartol A, Liebler SS, Brütsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A (2010) Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A 107: 12640-12645.

Brütsch R*, Liebler SS*, Wüstehube J*, Bartol A, Herberich SE, Adam MG, Telzerow A, Augustin HG, Fischer A (2010) Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis. Circ Res 107: 592-601.

Fischer A, Steidl C, Wagner TU, Lang E, Jakob PM, Friedl P, Knobeloch KP, Gessler M (2007) Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circ Res 100: 856-863.

Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 18: 901-911.

All publications (in chronological order)

Weis EM, Puchalska P, Nelson A, Taylor J, Moll I, Hasan SS, Dewenter M, Hagenmueller M, Fleming T, Poschet G, Hotz-Wagenblatt A, Backs J, Crawford P, Fischer A. Ketone body oxidation increases cardiac endothelial cell proliferation. EMBO Mol Med. 2022 in press.

Hollstein MM, Münsterkötter L, Schön MP, Bergmann A, Husar TM, Abratis A, Eidizadeh A, Schaffrinski M, Zachmann K, Schmitz A, Holsapple JS, Stanisz-Bogeski H, Schanz J, Fischer A, Groß U, Leha A, Zautner AE, Schnelle M*, Erpenbeck L*. Interdependencies of cellular and humoral immune responses in heterologous and homologous SARS‑CoV‑2 vaccination. Allergy 2022​, in press.

Laban H, Siegmund S, Zappe M, Trogisch FA, Heineke H, De La Torre C, Fisslthaler B, Arnold C, Lauryn J, Büttner M, Mogler C, Kato K, Adams RH, Kuk H, Fischer A, Hecker M, Kuebler WM, Korff T. NFAT5/TonEBP limits pulmonary vascular resistance in the hypoxic lung by controlling mitochondrial reactive oxygen species generation in arterial smooth muscle cells. Cells. 10(12):3293. doi: 10.3390/cells10123293. 2021

Kappert L, Ruzicka P, Kutikhin A, Feldner A, Sticht C, Fischer A, Hecker M, Arnold C, Korff T. Loss of Nfat5 promotes lipid accumulation in vascular smooth muscle cells. FASEB. 35(9):e21831. 2021

Alsina-Sanchis E, Mülfarth R, Fischer A. Control of Tumor Progression by Angiocrine Factors. Cancers(Basel) 13(11):2610. doi: 10.3390/cancers13112610. [cover story]

Alsina Sanchis E, Mülfarth R, Moll I, Mogler C, Rodriguez-Vita J*, Fischer A*: Intraperitoneal oil application causes local inflammation with depletion of resident peritoneal macrophages. Mol Cancer Res. 19(2):288-300. doi: 10.1158/1541-7786.MCR-20-0650. [cover story]

Hubert MO, Rodriguez-Vita J, Wiedmann L, Fischer A: Isolation of murine primary aortic smooth muscle cells. BioProtocol. 11(3):e3907. doi: 10.21769/BioProtoc.3907. [cover story]

Morgenstern J, Fleming T, Kliemank E, Brune M, Nawroth PP, Fischer A: Quantification of all-trans retinoic acid by liquid chromatography-tandem mass spectrometry and association with lipid profile in patients with type 2 diabetes. Metabolites. 11(1), 60; 2021.

Hasan SS, Fischer A: The endothelium: an active regulator of lipid and glucose homeostasis. Trends Cell Biol. 31(1):37-49. 2021

Gonzalo-Juan I, Xie F, Becker M, Tulyaganov DU, Ionescu E, Lauterbach S, De Angelis Rigotti F, Fischer A, Riedel R: Synthesis of silver modified bioactive glassy materials with antibacterial properties via facile and low-temperature route. Materials. 13(22):5115. 2020.

Hasan SS, Fischer A: Notch signaling in familial cerebral cavernous malformations and immunohistochemical detection of cleaved Notch intracellular domain. Methods Mol Biol.2152:427-435, 2020

Hasan SS*, Jabs M*, Taylor J, Wiedmann L, Leibing T, Nordström V, Federico G, Roma LP, Carlein C, Wolff G, Ekim-Üstünel B, Brune M, Moll I, Tetzlaff F, Gröne H-J, Fleming T, Géraud C, Herzig S, Nawroth PP, Fischer A: Endothelial Notch signaling controls insulin transport in muscle. EMBO Mol Med, 12(4):e09271., 2020.

Taylor J, Fischer A: EC dictate cardiac fuel source. Aging, 11: 1083-4, 2019

Klose R, Prinz A, Tetzlaff F, Weis EM, Moll I, Rodriguez-Vita J, Oka C, Korff T, Fischer A: Loss of the serine protease HTRA1 impairs smooth muscle cells maturation. Sci Rep. Dec 3;9(1):18224. 2019

Tetzlaff F and Fischer A: Human EC spheroid-based sprouting angiogenesis assay in collagen. BioProtocol, 8(17), 2018.

Klose R, Adam MG, Weis EM, Moll I, Wüstehube-Lausch J, Tetzlaff F, Oka C, Ehrmann M, Fischer A: Inactivation of the serine protease HTRA1 inhibits tumor growth by deregulating angiogenesis. Oncogene, 37: 4260-72, 2018.

Jabs M, Rose AJ, Lehmann LH, Taylor J, Moll I, Sijmonsma TP, Herberich SE, Sauer SW, Poschet G, Federico G, Mogler C, Weis EM, Augustin HG, Yan M, Gretz N, Schmid RM, Adams RH, Gröne HJ, Hell R, Okun JG, Backs J, Nawroth PP, Herzig S, Fischer A. (2018) Inhibition of endothelial Notch signaling impairs fatty acid transport and leads to metabolic and vascular remodeling of the adult heart. Circulation. Jun 12;137(24):2592-2608.

Tetzlaff F, Adam MG, Feldner A, Moll I, Menuchin A, Rodriguez-Vita J, Sprinzak D, Fischer A. (2018) MPDZ promotes DLL4-induced Notch signaling during angiogenesis. eLife. Apr 5;7. pii: e32860.

Tetzlaff F, Fischer A: Control of blood vessel formation by Notch signaling. Adv Exp Med Biol, 1066: 319-338, 2018.

Fischer A, Braga VMM: Vascular permeability: Flow-mediated, non-canonical notch signaling promotes barrier integrity. Curr Biol, 28: R119-R121, 2018.

Fischer A, Nawroth PP: Chapters 31, 33, 42,47 and 54 in Kihm L, Kopf S, Nawroth PP (Ed.), Diabetes-Therapie – informiert entscheiden. Patientenzentriertes und fallbasiertes Vorgehen über Leitlinien hinaus. Springer. Berlin Heidelberg. 2018

Feldner A, Adam MG, Tetzlaff F, Moll I, Komljenovic D, Sahm F, Bäuerle T, Ishikawa H, Schroten H, Korff T, Hofmann I, Wolburg H, von Deimling A, Fischer A. Loss of Mpdz impairs ependymal cell integrity leading to perinatal-onset hydrocephalus in mice. EMBO Mol Med. Jul;9(7):890-905., 2017

Wieland E*, Rodriguez-Vita J*, Liebler SS, Mogler C, Moll I, Herberich SE, Espinet E, Herpel E, Menuchin A, Chang-Claude J, Hoffmeister M, Gebhardt C, Brenner H, Trumpp A, Siebel CW, Hecker M, Utikal J, Sprinzak D, Fischer A: Endothelial Notch1 activity facilitates metastasis. Cancer Cell, 3: 355-367, 2017. 

Rodriguez Vita J, Tetzlaff F, Fischer A (2017) Notch controls endothelial cells. Oncoscience. Jun 25;4(5-6):45-46.

Rodriguez Vita J, Fischer A (2017) Notch1 induces endothelial senescence and promotes tumor progression. Cell Cycle. May 19;16(10):911-912, 2017

Rodriguez Vita J, Fischer A (2017) Notch signaling facilitates crossing of endothelial barriers by tumor cells. Mol Cell Oncol. Apr 3;4(3):e1311828.

Spiegler S, Kirchmaier B, Rath M, Korenke GC, Tetzlaff F, van de Vorst M, Neveling K, Acker-Palmer A, Kuss AW, Gilissen C, Fischer A, Schulte-Merker S, Felbor U. (2016) FAM222B is not a likely novel candidate gene for cerebral cavernous malformations. Mol Syndrom. Jul;7(3):144-52.

Herberich SE*, Klose R*, Moll I, Yang W-J, Wüstehube-Lausch J, Fischer A (2015) ANKS1B interacts with the cerebral cavernous malformation protein-1 and controls endothelial permeability but not sprouting angiogenesis. PLoS One.10(12):e0145304.

Yang W-J*, Hu J*, Uemura A, Tetzlaff F, Augustin HG, Fischer A (2015) Semaphorin-3C signals through Neuropilin-1 and PlexinD1 receptors to inhibit pathological angiogenesis. EMBO Mol Med. 7 (10):1267-1284.

 Fischer A. Physiologie Band 6, Herz und Kreislauf, 7. Auflage, MEDI-LEARN Verlag, Marburg.

Klose R*, Berger C*, Moll I, Adam MG, Schwarz F, Mohr K, Augustin HG, Fischer A (2015) Soluble Notch ligand and receptor peptides act antagonistically during angiogenesis. Cardiovasc Res. 107(1):153-163.

Wöltje K*, Jabs M*, Fischer A (2015) Serum induces transcription of Hey1 and Hey2 genes by Alk1 but not Notch signaling in endothelial cells. PLoS One. 10 (3): e0120547.

Schulz GB, Wieland E, Wüstehube-Lausch J, Boulday G, Moll I, Tournier-Lasserve E, Fischer A (2015) Cerebral cavernous malformation-1 protein controls DLL4-Notch3 signaling between the endothelium and pericytes. Stroke. 46(5):1337-1343.

Adam MG, Berger C, Feldner A, Yang W-J, Wüstehube-Lausch J, Herberich SE, Pinder M, Gesierich S, Hammes H-P, Augustin HG, Fischer A (2013) Synaptojanin-2 binding protein stabilizes the Notch ligands DLL1 and DLL4 and inhibits sprouting angiogenesis. Circ Res. 113: 1206-1218.

Schaafhausen MK, Yang WJ, Centanin L, Wittbrodt J, Bosserhoff A, Fischer A, Schartl M, Meierjohann S (2013) Tumor angiogenesis is caused by single melanoma cells in a reactive oxygen species and NF-κB dependent manner. J Cell Sci. 126: 3862-3872.

Fischer A, Zalvide J, Faurobert E, Albiges-Rizo C, Tournier-Lasserve E (2013) Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis. Trends Mol Med 19 (13): 302-308.

Liebler SS, Feldner A, Adam MG, Korff T, Augustin HG, Fischer A (2012) No evidence for a functional role of bi-directional Notch signaling during angiogenesis. PLoS One. 7 (12): e53074.

Wagner TU*, Fischer A*, Thoma EC, Schartl M (2011) Cross Query: a web tool for easy associative querying of transcriptome data. PLoS One 6: e28990.

Thoma EC, Wagner TU, Weber IP, Herpin A, Fischer A, Schartl, M(2011) Ectopic expression of single transcription factors directs differentiation of a medaka spermatogonial cell line. Stem Cells Dev 20: 1425-1438.

Schleider E, Stahl S, Wüstehube J, Walter U, Fischer A, Felbor U (2011) Evidence for anti- angiogenic and pro-survival functions of the cerebral cavernous malformation protein 3. Neurogenetics 12: 83-86.

Wüstehube J, Bartol A, Liebler SS, Brütsch R, Zhu Y, Felbor U, Sure U, Augustin HG, Fischer A (2010) Cerebral cavernous malformation protein CCM1 inhibits sprouting angiogenesis by activating DELTA-NOTCH signaling. Proc Natl Acad Sci U S A 107: 12640-12645.

Brütsch R*, Liebler SS*, Wüstehube J*, Bartol A, Herberich SE, Adam MG, Telzerow A, Augustin HG, Fischer A (2010) Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis. Circ Res 107: 592-601.

Coulpier F, Le Crom S, Maro GS, Manent J, Giovannini M, Maciorowski Z, Fischer A, Gessler M, Charnay P, Topilko P (2009) Novel features of boundary cap cells revealed by the analysis of newly identified molecular markers. Glia 57: 1450-1457.

Fischer A, Steidl C, Wagner TU, Lang E, Jakob PM, Friedl P, Knobeloch KP, Gessler M (2007) Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circ Res 100: 856-863.

Diez H, Fischer A, Winkler A, Hu CJ, Hatzopoulos AK, Breier G, Gessler M (2007) Hypoxia- mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp Cell Res 313: 1-9.

Rutenberg JB, Fischer A, Jia H, Gessler M, Zhong TP, Mercola M (2006) Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors. Development 133: 4381-4390.

Fischer A, Klattig J, Kneitz B, Diez H, Maier M, Holtmann B, Englert C, Gessler M (2005) Hey basic helix-loop-helix transcription factors are repressors of GATA4 and GATA6 and restrict expression of the GATA target gene ANF in fetal hearts. Mol Cell Biol 25: 8960-8970.

Fischer A, Klamt B, Schumacher N, Glaeser C, Hansmann I, Fenge H, Gessler M (2004) Phenotypic variability in Hey2 -/- mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome. Mamm Genome 15: 711-716.

Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 18: 901-911.

Schlaeger TM, Schuh A, Flitter S, Fischer A, Mikkola H, Orkin SH, Vyas P, Porcher C (2004) Decoding hematopoietic specificity in the helix-loop-helix domain of the transcription factor SCL/Tal-1. Mol Cell Biol 24: 7491-7502.

Popp H, Kalb R, Fischer A, Lobitz S, Kokemohr I, Hanenberg H, Schindler D (2003) Screening Faconi anemia lymphoid cell lines of non-A, C, D2, E, F, G subtypes for defects in BRCA2/FANCD1. Cytogenet Genome Res 103: 54-57.

Van Wayenbergh R, Taelman V, Pichon B, Fischer A, Kricha S,Gessler M(2003) Identification of BOIP, a novel cDNA highly expressed during spermatogenesis that encodes a protein interacting with the orange domain of the hairy-related transcription factor HRT/Hey1 in Xenopus and mouse. Dev Dyn 228: 716-725.

Gessler M, Knobeloch KP, Helisch A, Amann K, Schumacher N, Rohde E, Fischer A, Leimeister C (2002) Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2 -/- mice. Curr Biol 12: 1601-1604.

Leimeister C, Dale K, Fischer A, Klamt B, Hrabe de Angelis M, Radtke F, McGrew MJ, Pourquie O, Gessler M (2000) Oscillating expression of c-Hey2 in the presomitic mesoderm suggests that the segmentation clock may use combinatorial signaling through multiple interacting bHLH factors. Dev Biol 227: 91-103.

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