Blood Vessels; Cardiology; Central Nervous System; Endothelium, Vascular; Physiology
Vertebrate blood vessels form stereotyped, hierarchical branched networks. Specialized endothelial cells (EC) called tip cells located at the extremities of growing capillary sprouts mediate their directional outgrowth. Following behind tip cells, other EC termed stalk cells form the capillary lumen and proliferate. Specific gene expression profiles in tip and stalk cells allow them to acquire their characteristic morphological features. Tip cells also show similarities to axonal growth cones and express receptors for axon guidance cues. Research in my lab is aimed at understanding the function of tip cell-specific signaling molecules, with the goal to manipulate guided vascular patterning. Another focus in the laboratory is to understand functions of vascular endothelial growth factors in the nervous system.
Specialized Terms: Vascular development and angiogenesis; Guidance of vascular patterning; Tip cells; Axonal growth cones; Vascular growth factors in the nervous system
Extensive Research Description
Guidance of vascular patterning
Specialized endothelial cells (EC) called tip cells located at the extremities of growing capillary sprouts mediate guided vascular patterning. Tip cells exhibit characteristic features, including extension of filopodia that explore the tip cell environment, lack of a lumen and a slow proliferation rate. Following behind tip cells, other EC termed stalk cells form the capillary lumen and proliferate. Tip cell selection is induced by VEGF signaling through VEGFR2. We and others have shown that tip cells also express high levels of the endothelial-specific Notch ligand Delta-like 4 (Dll4). Inactivation of one allele of the Dll4 gene in mice and pharmacological inhibition of Notch signaling using gamma-secretase inhibitors causes excessive tip cell formation. Dll4 inactivation leads to alterations in VEGF receptor levels, suggesting that Dll4 negatively regulates the sensitivity of ECs to VEGF and so acts as a ‘brake’ on VEGF signaling during capillary sprouting to ensure that only a limited number of cells form tips. Isolation of EC from dll4+/- mice has allowed us to identify novel tip-cell enriched genes, the function of which we are currently investigating.
Capillary sprouting also shows morphological similarities to axon guidance. Like endothelial tip cells, axonal growth cones extend filopodia that sense and respond to extracellular guidance cues. By screening for the expression of axon guidance molecules in EC, we have identified several key molecules regulating capillary guidance. The Netrin receptor UNC5B is expressed in arterial EC and in tip cells. Loss of function of Unc5b in mouse and zebrafish embryos leads to ectopic filopodial extension from endothelial tip cells and excessive blood vessel branching. Treatment of endothelial tip cells with the UNC5B ligand Netrin-1 leads to filopodial retraction, an effect that is lost in Unc5b mutants. UNC5B thus functions as a repulsive guidance receptor controlling morphogenesis of the vascular system. The capacity to direct blood vessel growth may have important therapeutic implications for the anti-angiogenic treatment of solid tumors. We are currently studying a novel UNC5B ligand that we have identified.
My group has also shown the selective expression of the VEGF co-receptors Neuropilin (Nrp) in EC of arteries (Nrp1) and of veins/lymphatics (Nrp2). Homozygous Nrp2 mutant embryos exhibit selective defects in the formation of lymphatic vessels, while their veins and arteries form normally. Lymphatic vessels are aberrantly positioned and enlarge rather than form branches. Antibodies blocking VEGF-C binding to Nrp2 and Nrp2-Vegfr3 double heterozygous mice reproduce these defects, indicating that binding of VEGF to Nrp2 and signal transduction through VEGFR3 mediate lymphatic vessel sprouting. We have generated transgenic mice expressing GFP in their lymphatic vessels to analyze live lymphatic vessel development in normal and mutant animals by multiphoton imaging.
Vascular endothelial growth factors including VEGF-C also regulate development of certain neuronal cell types. We are using targeted inactivation of Vegfr3 in neural cells to understand VEGF-C/VEGFR-3 signaling in the nervous system.Functional analysis of novel tip-cell enriched genes
UNC5B signaling and function
NRPs in the vascular and lymphatic system
Real-time imaging of lymphatic vessel development
Role of vascular growth factors in the nervous system
Alk1 signaling inhibits angiogenesis by cooperating with the Notch pathway.
Larrivée B, Prahst C, Gordon E, del Toro R, Mathivet T, Duarte A, Simons M, Eichmann A. Alk1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev. Cell 2012, 22: 489-500.
Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis.
Calvo CF, Fontaine RH, Soueid J, Tammela T, Makinen T, Alfaro-Cervello C, Bonnaud F, Miguez A, Benhaim L, Xu Y, Barallobre MJ, Moutkine I, Lyytikkä J, Tatlisumak T, Pytowski B, Zalc B, Richardson W, Kessaris N, Garcia-Verdugo JM, Alitalo K, Eichmann A, Thomas JL. Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis. Genes & Dev. 2011, 25: 831-844.
Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B.
Koch AW, Mathivet T, Larrivée B, Tong RK, Kowalski J, Pibouin-Fragner L, Bouvrée K, Stawicki S, Nicholes K, Rathore N, Scales SJ, Luis E, del Toro R, Freitas C, Bréant C, Michaud A, Corvol P, Thomas JL, Wu J, Peale F, Watts RJ, Tessier-Lavigne M, Bagri A, Eichmann, A. Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. Dev. Cell 2011, 20: 33-46.
The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching.
Suchting S, Freitas C, LeNoble F, Benedito R, Bréant C, Duarte A, Eichmann A. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc. Natl. Acad. Sci. USA 2007; 104: 3225-3230.
The Netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system.
Lu X, LeNoble F, Yuan L, Jiang Q, de Lafarge B, Sugiyama D, Bréant C, Claes F, De Smet F, Thomas JL, Autiero M, Carmeliet P, Tessier-Lavigne M, Eichmann A. The Netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 2004; 432: 179-186.
Full List of PubMed Publications
- Antila S, Karaman S, Nurmi H, Airavaara M, Voutilainen MH, Mathivet T, Chilov D, Li Z, Koppinen T, Park JH, Fang S, Aspelund A, Saarma M, Eichmann A, Thomas JL, Alitalo K: Development and plasticity of meningeal lymphatic vessels. J Exp Med. 2017 Nov 15; 2017 Nov 15. PMID: 29141865
- Greif DM, Eichmann A: Basic research: Where do new endothelial cells come from in the injured heart? Nat Rev Cardiol. 2017 Sep; 2017 Aug 3. PMID: 28770866
- Yu P, Wilhelm K, Dubrac A, Tung JK, Alves TC, Fang JS, Xie Y, Zhu J, Chen Z, De Smet F, Zhang J, Jin SW, Sun L, Sun H, Kibbey RG, Hirschi KK, Hay N, Carmeliet P, Chittenden TW, Eichmann A, Potente M, Simons M: FGF-dependent metabolic control of vascular development. Nature. 2017 May 11; 2017 May 3. PMID: 28467822
- Lee HW, Chong DC, Ola R, Dunworth WP, Meadows S, Ka J, Kaartinen VM, Qyang Y, Cleaver O, Bautch VL, Eichmann A, Jin SW: Alk2/ACVR1 and Alk3/BMPR1A Provide Essential Function for Bone Morphogenetic Protein-Induced Retinal Angiogenesis. Arterioscler Thromb Vasc Biol. 2017 Apr; 2017 Feb 23. PMID: 28232325
- Ola R, Dubrac A, Han J, Zhang F, Fang JS, Larrivée B, Lee M, Urarte AA, Kraehling JR, Genet G, Hirschi KK, Sessa WC, Canals FV, Graupera M, Yan M, Young LH, Oh PS, Eichmann A: PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nat Commun. 2016 Nov 29; 2016 Nov 29. PMID: 27897192
- Zhang F, Prahst C, Mathivet T, Pibouin-Fragner L, Zhang J, Genet G, Tong R, Dubrac A, Eichmann A: The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization. Nat Commun. 2016 Nov 24; 2016 Nov 24. PMID: 27882935
- Kraehling JR, Chidlow JH, Rajagopal C, Sugiyama MG, Fowler JW, Lee MY, Zhang X, Ramírez CM, Park EJ, Tao B, Chen K, Kuruvilla L, Larriveé B, Folta-Stogniew E, Ola R, Rotllan N, Zhou W, Nagle MW, Herz J, Williams KJ, Eichmann A, Lee WL, Fernández-Hernando C, Sessa WC: Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells. Nat Commun. 2016 Nov 21; 2016 Nov 21. PMID: 27869117
- Baeyens N, Larrivée B, Ola R, Hayward-Piatkowskyi B, Dubrac A, Huang B, Ross TD, Coon BG, Min E, Tsarfati M, Tong H, Eichmann A, Schwartz MA: Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J Cell Biol. 2016 Sep 26; 2016 Sep 19. PMID: 27646277
- Ntumba K, Akla N, Oh SP, Eichmann A, Larrivée B: BMP9/ALK1 inhibits neovascularization in mouse models of age-related macular degeneration. Oncotarget. 2016 Aug 30. PMID: 27517154
- Pardanaud L, Pibouin-Fragner L, Dubrac A, Mathivet T, English I, Brunet I, Simons M, Eichmann A: Sympathetic Innervation Promotes Arterial Fate by Enhancing Endothelial ERK Activity. Circ Res. 2016 Aug 19; 2016 Jun 27. PMID: 27354211
- Sun H, Zhu Y, Pan H, Chen X, Balestrini JL, Lam TT, Kanyo JE, Eichmann A, Gulati M, Fares WH, Bai H, Feghali-Bostwick CA, Gan Y, Peng X, Moore MW, White ES, Sava P, Gonzalez AL, Cheng Y, Niklason LE, Herzog EL: Netrin-1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin-Induced Pulmonary Fibrosis. Arthritis Rheumatol. 2016 May. PMID: 26749424
- Li N, Hwangbo C, Jaba IM, Zhang J, Papangeli I, Han J, Mikush N, Larrivée B, Eichmann A, Chun HJ, Young LH, Tirziu D: miR-182 Modulates Myocardial Hypertrophic Response Induced by Angiogenesis in Heart. Sci Rep. 2016 Feb 18; 2016 Feb 18. PMID: 26888314
- Dubrac A, Genet G, Ola R, Zhang F, Pibouin-Fragner L, Han J, Zhang J, Thomas JL, Chedotal A, Schwartz MA, Eichmann A: Targeting NCK-Mediated Endothelial Cell Front-Rear Polarity Inhibits Neovascularization. Circulation. 2016 Jan 26; 2015 Dec 9. PMID: 26659946
- Fortuna V, Pardanaud L, Brunet I, Ola R, Ristori E, Santoro MM, Nicoli S, Eichmann A: Vascular Mural Cells Promote Noradrenergic Differentiation of Embryonic Sympathetic Neurons. Cell Rep. 2015 Jun 23; 2015 Jun 11. PMID: 26074079
- Aspalter IM, Gordon E, Dubrac A, Ragab A, Narloch J, Vizán P, Geudens I, Collins RT, Franco CA, Abrahams CL, Thurston G, Fruttiger M, Rosewell I, Eichmann A, Gerhardt H: Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch. Nat Commun. 2015 Jun 17; 2015 Jun 17. PMID: 26081042
- Simons M, Eichmann A: Molecular controls of arterial morphogenesis. Circ Res. 2015 May 8. PMID: 25953926
- Rama N, Dubrac A, Mathivet T, Ní Chárthaigh RA, Genet G, Cristofaro B, Pibouin-Fragner L, Ma L, Eichmann A, Chédotal A: Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization. Nat Med. 2015 May; 2015 Apr 20. PMID: 25894826
- Han J, Calvo CF, Kang TH, Baker KL, Park JH, Parras C, Levittas M, Birba U, Pibouin-Fragner L, Fragner P, Bilguvar K, Duman RS, Nurmi H, Alitalo K, Eichmann AC, Thomas JL: Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans. Cell Rep. 2015 Feb 24; 2015 Feb 19. PMID: 25704818
- Baeyens N, Nicoli S, Coon BG, Ross TD, Van den Dries K, Han J, Lauridsen HM, Mejean CO, Eichmann A, Thomas JL, Humphrey JD, Schwartz MA: Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point. Elife. 2015 Feb 2; 2015 Feb 2. PMID: 25643397
- Lanahan AA, Lech D, Dubrac A, Zhang J, Zhuang ZW, Eichmann A, Simons M: PTP1b is a physiologic regulator of vascular endothelial growth factor signaling in endothelial cells. Circulation. 2014 Sep 9; 2014 Jun 30. PMID: 24982127
- Eichmann A, Brunet I: Arterial innervation in development and disease. Sci Transl Med. 2014 Sep 3. PMID: 25186174
- Lee MY, Luciano AK, Ackah E, Rodriguez-Vita J, Bancroft TA, Eichmann A, Simons M, Kyriakides TR, Morales-Ruiz M, Sessa WC: Endothelial Akt1 mediates angiogenesis by phosphorylating multiple angiogenic substrates. Proc Natl Acad Sci U S A. 2014 Sep 2; 2014 Aug 18. PMID: 25136137
- Prahst C, Kasaai B, Moraes F, Jahnsen ED, Larrivee B, Villegas D, Pardanaud L, Pibouin-Fragner L, Zhang F, Zaun HC, Eichmann A, Jones EA: The H2.0-like homeobox transcription factor modulates yolk sac vascular remodeling in mouse embryos. Arterioscler Thromb Vasc Biol. 2014 Jul; 2014 Apr 24. PMID: 24764455
- Greif DM, Eichmann A: Vascular biology: Brain vessels squeezed to death. Nature. 2014 Apr 3; 2014 Mar 26. PMID: 24670635
- Eichmann A, Simons M: Need glucose to sprout: local metabolic control of angiogenesis. EMBO Mol Med. 2013 Oct; 2013 Aug 27. PMID: 23982994
- Atri D, Larrivée B, Eichmann A, Simons M: Endothelial signaling and the molecular basis of arteriovenous malformation. Cell Mol Life Sci. 2013 Sep 28; 2013 Sep 28. PMID: 24077895
- Simons M, Eichmann A: Physiology. Lymphatics are in my veins. Science. 2013 Aug 9. PMID: 23929973
- Deng Y, Larrivée B, Zhuang ZW, Atri D, Moraes F, Prahst C, Eichmann A, Simons M: Endothelial RAF1/ERK activation regulates arterial morphogenesis. Blood. 2013 May 9; 2013 Mar 25. PMID: 23529931
- Thomas JL, Baker K, Han J, Calvo C, Nurmi H, Eichmann AC, Alitalo K: Interactions between VEGFR and Notch signaling pathways in endothelial and neural cells. Cell Mol Life Sci. 2013 May; 2013 Mar 12. PMID: 23479133
- Thomas JL, Eichmann A: The power of VEGF (vascular endothelial growth factor) family molecules. Cell Mol Life Sci. 2013 May; 2013 Mar 12. PMID: 23475064
- Deng Y, Atri D, Eichmann A, Simons M: Endothelial ERK signaling controls lymphatic fate specification. J Clin Invest. 2013 Mar; 2013 Feb 8. PMID: 23391722
- Eichmann A, Thomas JL: Molecular parallels between neural and vascular development. Cold Spring Harb Perspect Med. 2013 Jan 1; 2013 Jan 1. PMID: 23024177
- Tirziu D, Jaba IM, Yu P, Larrivée B, Coon BG, Cristofaro B, Zhuang ZW, Lanahan AA, Schwartz MA, Eichmann A, Simons M: Endothelial nuclear factor-κB-dependent regulation of arteriogenesis and branching. Circulation. 2012 Nov 27; 2012 Oct 22. PMID: 23091063
- Kim JD, Kang H, Larrivée B, Lee MY, Mettlen M, Schmid SL, Roman BL, Qyang Y, Eichmann A, Jin SW: Context-dependent proangiogenic function of bone morphogenetic protein signaling is mediated by disabled homolog 2. Dev Cell. 2012 Aug 14. PMID: 22898784
- Eichmann A, Simons M: VEGF signaling inside vascular endothelial cells and beyond. Curr Opin Cell Biol. 2012 Apr; 2012 Feb 25. PMID: 22366328
- Larrivée B, Prahst C, Gordon E, del Toro R, Mathivet T, Duarte A, Simons M, Eichmann A: ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev Cell. 2012 Mar 13. PMID: 22421041