List of selected publications per research group.
Korhonen EA, Murtomäki A, Jha SK, Anisimov A, Pink A, Zhang Y, Stritt S, Liaqat I, Stanczuk L, Alderfer L, Sun Z, Kapiainen E, Singh A, Sultan I, Lantta A, Leppänen VM, Eklund L, He Y, Augustin HG, Vaahtomeri K, Saharinen P, Mäkinen T, Alitalo K. Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression. J Clin Invest. 2022;132(15):e155478.
Leppänen VM*, Brouillard P*, Korhonen EA, Sipilä T, Kumar Jha S, Revencu N, Labarque V, Fastré E, Schlögel M, Ravoe M, Singer A, Luzzatto C, Angelone D, Giovanni Crichiutti G, D’Elia A, Kuurne J, Elamaa H, Koh GY, Saharinen P, Vikkula M#, Alitalo K#. Characterization of ANGPT2 mutations associated with primary lymphedema. Sci Transl Med. 2020;12:eaax8013. * # Equal contribution
Li Z*,Korhonen EA*, Merlini A, Strauss J, Wihuri E, Nurmi H, Antila S, Paech J, Deutsch U, Engelhardt B, Chintharlapalli S, Koh GY, Flügel A, Alitalo K. Angiopoietin-2 blockade ameliorates autoimmune neuroinflammation by inhibiting leukocyte recruitment into the CNS. J Clin Invest. 2020;130:1977-1990. * Equal contribution
Korhonen EA*, Lampinen A*, Giri H, Anisimov A, Kim M, Allen B, Fang S, D’Amico G, Sipilä TJ, Lohela M, Strandin T, Vaheri A, Ylä-Herttuala S, Koh GY, McDonald DM, Alitalo K#, Saharinen P#. Tie1 controls angiopoietin function in vascular remodeling and inflammation. J Clin Invest. 2016;126:3495-510. * # Equal contribution
D’Amico G, Korhonen EA, Anisimov A, Zarkada G, Holopainen T, Hägerling R, Kiefer F, Eklund L, Sormunen R, Elamaa H, Brekken RA, Adams RH, Koh GY, Saharinen P and Alitalo K. Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy. J Clin Invest. 2014;124:824-834.
Antila, S, Chilov, D, Nurmi H, Li Z, Näsi A, Gotkiewicz M, Sitnikova V, Jäntti H, Acosta N, Koivisto H, Ray J, Keuters MH, Sultan I, Scoyni F, Trevisan D, Wojciechowski S, Kaakinen M, Dvořáková L, Singh A, Jukkola J, Korvenlaita N, Eklund L, Koistinaho J, Karaman S, Malm T, Tanila H, Alitalo K. Sustained meningeal lymphatic vessel atrophy or expansion does not alter Alzheimer’s disease-related amyloid pathology. Nat Cardiovasc Res 3: 474-491, 2024.
Brakenhielm E, Sultan I, Alitalo K. Cardiac Lymphangiogenesis in CVDs. Arterioscler Thromb Vasc Biol. 44:1016-1020, 2024.
Sultan I, Ramste M, Peletier P, Hemanthakumar KA, Ramanujam D, Tirronen A, von Wright Y, Antila S, Saharinen P, Eklund L, Mervaala E, Ylä-Herttuala S, Engelhardt S, Kivelä R, Alitalo K. Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy. Circ Res. 134:1465-1482, 2024.
Anisimov A, Fang S, Hemanthakumar KA, Örd T, van Avondt K, Chevre R, Toropainen A, Singha P, Gilani H, Nguyen SD, Karaman S, Korhonen EA, Adams RH, Augustin HG, Öörni K, Soehnlein O, Kaikkonen MU, Alitalo K. The angiopoietin receptor Tie2 is atheroprotective in arterial endothelium. Nat Cardiovasc Res. 2:307-321, 2023.
Li Z, Antila S, Nurmi H, Chilov D, Korhonen EA, Fang S, Karaman S, Engelhardt B, Alitalo K. Blockade of VEGFR3 signaling leads to functional impairment of dural lymphatic vessels without affecting autoimmune neuroinflammation. Sci Immunol. 8:eabq0375, 2023.
Leppäpuska IM, Hartiala P, Suominen S, Suominen E, Kaartinen I, Mäki M, Seppänen M, Kiiski J, Viitanen T, Lahdenperä O, Vuolanto A, Alitalo K, Saarikko AM. Phase 1 Lymfactin® study: 24-month efficacy and safety results of combined adenoviral VEGF-C and lymph node transfer treatment for upper extremity lymphedema. J Plast Reconstr Aesthet Surg. 75:3938-3945, 2022.
Results of phase I clinical trial on adenoviral VEGF-C in lymphedema.
Korhonen EA, Murtomäki A, Jha SK, Anisimov A, Pink A, Zhang Y, Stritt S, Liaqat I, Stanczuk L, Alderfer L, Sun Z, Kapiainen E, Singh A, Sultan I, Lantta A, Leppänen VM, Eklund L, He Y, Augustin HG, Vaahtomeri K, Saharinen P, Mäkinen T, Alitalo K. Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression. J Clin Invest. 132(15):e155478, 2022
This study explains the mechanism by which angiopoietin2 and Tie1 mutations cause lymphedema.
Leppänen VM, Brouillard P, Korhonen EA, Sipilä T, Jha SK, Revencu N, Labarque V, Fastré E, Schlögel M, Ravoet M, Singer A, Luzzatto C, Angelone D, Crichiutti G, D’Elia A, Kuurne J, Elamaa H, Koh GY, Saharinen P, Vikkula M, Alitalo K. Characterization of ANGPT2 mutations associated with primary lymphedema. Sci Transl Med 12: eaax8013, 2020.
Discovery of mutations in angiopoietin 2 growth factor gene in primary lymphedema patients
Antila S, Karaman S, Nurmi H, Airavaara M, Voutilainen MH, Mathivet T, Chilov D, Li Z, Koppinen T, Park J-H, Fang S, Aspelund A, Saarma M, Eichmann A, Thomas J-L, Alitalo K. Development and plasticity of meningeal lymphatic vessels. J Exp Med 214: 3645-3667, 2017.
Meningeal lymphatics develop postnatally and require continuous VEGF-C stimulation for maintenance.
Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212: 991-9, 2015.
Listed amongst the 10 Breakthroughs of 2015 by Science and as one of 10 Notable advances 2015 by Nature Medicine.
Aspelund A, Tammela T, Antila S Nurmi H, Leppänen VM, Zarkada G, Stanczuk L, Francois M, Mäkinen T, Saharinen P, Immonen I, Alitalo K. The Schlemm’s canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel. J Clin Invest 124: 3975-3986, 2014.
Schlemm’s canal that regulates intraocular pressure is a target of the lymphangiogenic growth factor VEGF-C.
Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppänen V-M, Holopainen T, Kivelä R, Ortega S, Kärpänen T, Alitalo K. CCBE1 enhances lymphangiogenesis via a disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation 129: 1962-1971, 2014.
Discovery of the first protease that activates VEGF-C and the mechanism of its regulation by CCBE1.
Leppänen V-M, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K, Alitalo K. Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Proc Natl Acad Sci USA 110: 12960-12965, 2013.
Atomic resolution structure of the VEGF-C/VEGFR3 complex reveals a homologous receptor-receptor interaction site that is compatible with blocking antibody function (Tvorogov et al., 2010).
Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, Zheng W, Franco CA, Murtomäki A, Aranda E, Miura N, Ylä-Herttuala S, Fruttiger M, Mäkinen T, Eichmann A, Pollard JW, Gerhardt H, Alitalo K. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nature Cell Biol 13: 1202-1213, 2011.
The mechanism of ligand-independent VEGFR-3 function in blood vessel fusions.
Tammela T, Saaristo A, Holopainen T, Ylä-Herttuala S, Andersson LC, Virolainen S, Immonen I, Alitalo K. Photodynamic ablation of lymphatic vessels and intralymphatic cancer cells prevents metastasis. Sci Transl Med 3: 69ra11, 2011.
A new method to inhibit in transit/satellite metastasis.
Tvorogov D, Anisimov A, Zheng W, Leppänen V-M, Tammela T, Laurinavicius S, Holnthoner W, Heloterä H, Holopainen T, Jeltsch M, Kalkkinen N, Lankinen H, Ojala P, Alitalo K. Effective Suppression of Vascular Network Formation by Combination of Antibodies Blocking VEGFR Ligand Binding and Receptor Dimerization. Cancer Cell 18: 630-40, 2010.
These results indicate that VEGF receptor directed antibodies that inhibit ligand binding and receptor dimerization have additive or even synergistic effects.
D’Amico G, Korhonen EA, Waltari M, Saharinen P, Laakkonen P, Alitalo K. Loss of endothelial Tie1 receptor impairs lymphatic vessel development-brief report. Arterioscler Thromb Vasc Biol. 30: 207-9, 2010
First indication that the Tie1 receptor is involved in lymphangiogenesis.
V-M Leppänen, A Prota, M Jeltsch, A Anisimov, N Kalkkinen, T Strandin, H Lankinen, A Goldman, K Ballmer-Hofer and K Alitalo: Structural determinants of growth factor binding and specificity by VEGF-Receptor 2. Proc Natl Acad Sci, USA, 107: 2425-2430, 2010.
The structure of VEGF-C, and its complex with the main angiogenic receptor VEGFR-2.
Tammela T, Zarkada G, Wallgard E, Murtomäki A, Suchting S, Wirzenius M, Waltari M, Hellström M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Ylä-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454: 656-60, 2008.
This paper reveals a new mechanism involved in blood vessel sprouting and provides an additional target for angiogenesis inhibition.
Tammela T, Saaristo A, Holopainen T, Lyytikkä J, Kotronen A, Pitkonen M, Abo-Ramadan U, Ylä-Herttuala S, Petrova TV, Alitalo K. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nature Medicine 13: 1458-66, 2007.
The first evidence that collecting lymphatic vessels can differentiate from lymphatic capillaries in adults and that VEGF-C gene therapy induces this process.
He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Ylä-Herttuala S, Harding T, Jooss K, Takahashi T, Alitalo K. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 65: 4739-46, 2005.
The mechanism of VEGF-C induced lymphatic sprouting towards as well as dilation of the draining lymphatic vessels, both contributing to lymphatic metastasis. These processes were blocked dose-dependently by inhibition of VEGFR-3.
Petrova TV, Kärpänen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, Ferrell R, Kerjaschki D, Mortimer P, Ylä-Herttuala S, Miura N, Alitalo K. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nature Medicine 10: 974-81, 2004.
Mechanism of development of Lymphedema distichiasis.
Kärkkäinen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunology 5: 74-80, 2004.
The results of this paper indicate that VEGF-C is the paracrine factor essential for lymphangiogenesis, and that both Vegfc alleles are required for normal lymphatic development.
He Y, Kozaki K, Kärpänen T, Koshikawa K, Ylä-Herttuala S, Takahashi T, Alitalo K. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 94: 819-25, 2002.
Development of VEGFR-3 signaling inhibitor for suppression of tumor lymphangiogenesis and metastasis to regional lymph nodes.
Mäkinen T, Jussila L, Veikkola T, Kärpänen T, Kettunen MI, Pulkkanen KJ, Kauppinen R, Jackson DG, Kubo H, Nishikawa S-I, Ylä-Herttuala S, Alitalo K. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nature Medicine 7: 199-205, 2001.
Demonstration that a soluble form of VEGFR-3 is a potent inhibitor of VEGF-C/VEGF-D signaling and lymphangiogenesis.
Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20: 672-82, 2001.
Demonstration that VEGF-C-induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.
Note the Acknowledgements:” The project presented in this manuscript was conceived and started in Helsinki, and the work is the result of an equal contribution from the laboratories in Helsinki, Vienna and Geneva, together with a major contribution from the Oxford group.” This project was thus started in 1995 in Dr. Alitalo’s laboratory.
Kärpänen T, Egeblad M, Kärkkäinen MJ, Kubo H, Ylä-Herttuala S, Jaattela M, Alitalo K. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61: 1786-90, 2001.
These data show that VEGF-C facilitates tumor metastasis to the lymphatic vessels and that tumor spread is inhibited by blocking the interaction between VEGF-C and its receptor.
Kärkkäinen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Ylä-Herttuala S, Finegold DN, Ferrell RE, Alitalo K. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci USA 98: 12677-82, 2001.
First demonstration that growth factor gene therapy would be applicable to human lymphedema and provide a paradigm for other diseases associated with mutant receptors.
Kärkkäinen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, Alitalo K, Finegold DN: Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nature Genetics 25: 153-159, 2000.
Heterozygous missense mutations of VEGFR-3 were shown to inactivate the tyrosine kinase and downstream gene activation in primary lymphedema, indicating that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema.
Dumont, DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K, Breitman M, Alitalo K. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282: 946-949, 1998.
This paper shows that VEGFR-3 has an essential role in the development of the embryonic cardiovascular system before the emergence of the lymphatic vessels.
Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Rakesh KJ, Alitalo K. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276: 1423-1425, 1997.
First evidence that VEGF-C induces lymphangiogenesis.
Joukov V, Pajusola K, Kaipainen, Chilov DA, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15: 290-298, 1996.
Isolation of the first ligand for VEGFR3.
Joukov V, Pajusola K, Kaipainen, Chilov DA, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 15: 290-298, 1996.
Isolation of VEGF-C, the first ligand for VEGFR3.
Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VWM, Fang G-H, Dumont D, Breitman M, Alitalo K. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci 92: 3566-3570, 1995.
First evidence that VEGFR3 mediated signals are selective for lymphatic vessels in adults.
Partanen J, Armstrong E, Mäkelä TP, Korhonen J, Sandberg M, Renkonen R, Knuutila S, Huebner K, Alitalo K. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol 12: 1698-1707, 1992.
Discovery of the endothelial Tie receptor (later renamed Tie1)
Aprelikova O, Pajusola K, Partanen J, Armstrong E, Alitalo R, Bailey SK, McMahon J, Wasmuth J, Huebner K, Alitalo K. FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-qter. Cancer Res. 52(3):746-8, 1992.
Discovery of vascular endothelial growth factor receptor 3.
Spatially targeted chemokine exocytosis guides transmigration at lymphatic endothelial multicellular junctions. Liaqat I., Hilska I., Jakobsson E., Saario M., Crivaro M., Peränen J., Vaahtomeri K. The EMBO Journal. 43(15):3141-3174, 2024
DLL4-Notch3-WNT5B axis mediates bi-directional pro-metastatic crosstalk between melanoma and lymphatic endothelial cells. Alve S., Gramolelli S., Jukonen J., Juteau S., Pink A., Manninen A., Monto E., Lackman MH., Carpén O., Karaman S., Saharinen P., Vaahtomeri K. and Ojala PM.
JCI insight, 9(1):e171821, 2023.
Self-organized and directed branching results in optimal coverage in developing dermal lymphatic networks. Can Ucar M., Hannezo E. , Tiilikainen E., Liaqat I., Jakobsson E., Nurmi, H., Vaahtomeri K. Nature Communications, 21;14(1):5878, 2023
Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell surface expression. Korhonen E. A., Murtomäki A., Jha S.K., Anisimov A., Pink A., Zhang Y., Stritt S., Liaqat I., Stanczuk L., Alderfer L., Sun Z., Kapiainen E., Singh A., Sultan I., Lantta A., Leppänen V.M., Eklund L., He Y., Augustin H.G., Vaahtomeri K., Saharinen P., Mäkinen T., Alitalo K. 1 Aug 2022, J Clin Invest., 132(15):e155478.
Shape and function of interstitial chemokine CCL21 gradients are independent of heparan sulfates produced by lymphatic endothelium. Vaahtomeri K., Moussion C., Hauschild R., Sixt M. 25 Feb 2021, Front Immunol. 12:630002, 2021.
Locally triggered release of chemokine CCL21 promotes dendritic cell transmigration across lymphatic endothelia. Vaahtomeri K, Brown M, Hauschild R, De Vries I, Leithner AF, Mehling M, Kaufmann WA, Sixt M. 2 May 2017, Cell Reports, 19(5):902-909.
CCL21 promotes tissue egress of intralymphatic dendritic cells through afferent lymphatic vessels. Russo E., Teijeira A., Vaahtomeri K., Wilbrodt, AH., Bloch, JS., Nitschke, M., Santambrogio, L., Kerjaschki, D., Sixt, M., Halin, C.”, 23 February 2016, Cell Reports, 14(7):1723-1734.
Dendritic cells interpret Haptotactic Chemokine Gradients in a manner governed by signal-to-noise ratio and dependent on GRK6. Schwarz J, Bierbaum V, Vaahtomeri K, Hauschild R, Brown M, de Vries I, Leithner A, Reversat A, Merrin J, Tarrant T, Bollenbach T, Sixt M. 8 May 2017, Current Biology, 27(9):1314-1325.
Lymphatic exosomes promote dendritic cell migration along guidance cues. Brown M, Johnson LA, Leone DA, Majek P, Vaahtomeri K, Senfter D, Bukosza N, Schachner H, Asfour G, Langer B, Hauschild R, Parapatics K, Hong YK, Bennett KL, Kain R, Detmar M, Sixt M, Jackson DG, Kerjaschki D. 4 June 2018, Journal of cell biology, 217(6):2205-2221.
Low-density lipoprotein particles carrying proinflammatory proteins with altered aggregation pattern detected in COVID-19 patients 3 months after hospitalization.
Ueland T, Äikäs LAO, Dahl TB, Gregersen I, Olsen MB, Michelsen A, Schanke Y, Holopainen M, Ruhanen H, Singh S; NOR-SOLIDARITY Consortium; Tveita AA, Finbråten AK, Heggelund L, Trøseid M, Dyrhol-Riise AM, Nyman TA, Holven KB, Öörni K, Aukrust P, Halvorsen B. J Infect. 2023 May;86(5):489-492. doi: 10.1016/j.jinf.2023.02.024.
The human liver lipidome is significantly related to the lipid composition and aggregation susceptibility of low-density lipoprotein (LDL) particles.
Lahelma M, Qadri S, Ahlholm N, Porthan K, Ruuth M, Juuti A, Orešič M, Hyötyläinen T, Öörni K, Yki-Järvinen H. (2022) Atherosclerosis ;363:22-29. doi: 10.1016/j.atherosclerosis.2022.11.018.
Modified Lipoproteins Induce Arterial Wall Inflammation During Atherogenesis.
Lorey MB, Öörni K, Kovanen PT.
Front Cardiovasc Med. 2022 Mar 3;9:841545. doi: 10.3389/fcvm.2022.841545. eCollection 2022.
Children with familial hypercholesterolemia display changes in LDL and HDL function: a cross-sectional study. Christensen JJ, Narverud I, Ruuth M, Heier M, Jauhiainen M, Ulven SM, Bogsrud MP, Kovanen PT, Halvorsen B, Oda MN, Wium C, Retterstøl K, Öörni K§, Holven KB§. (2021) J. Intern. Med. 290:1083-1097 doi: 10.1111/joim.13383
Overfeeding saturated fat increases LDL (Low-Density Lipoprotein) aggregation susceptibility while overfeeding unsaturated fat decreases proteoglycan-binding of lipoproteins. Ruuth M, Lahelma M, Luukkonen PK, Lorey MB, Qadri S, Sädevirta S, Hyötyläinen T, Kovanen PT, Hodson L, Yki-Järvinen H & Öörni K. (2021) Arterioscler. Thromb. Vasc. Biol. 11:2823-2836. doi: 10.1161/ATVBAHA.120.315766
Low-density lipoprotein aggregation predicts adverse cardiovascular events in peripheral artery disease. Heffron, S. P., Ruuth, M., Xia, Y., Hernandez, G., Rodriguez, C., Öörni, K.* & Berger, J. S.* (2021) Atherosclerosis 316:53-57. doi: 10.1016/j.atherosclerosis.2020.11.016
Lysophosphatidylcholine in phospholipase A 2-modified LDL triggers secretion of angiopoietin 2. Nguyen SD, Korhonen EA, Lorey MB, Hakanpää L, Mäyränpää MI, Kovanen PT, Saharinen P, Alitalo K & Öörni K. 2021, Atherosclerosis. 327:87-00. doi: 10.1016/j.atherosclerosis.2021.04.007
Plant stanol esters reduce LDL (Low-Density Lipoprotein) aggregation by altering LDL surface lipids: The BLOOD FLOW randomized intervention study. Ruuth M., Äikäs L., Tigistu-Sahle F., Käkelä R., Lindholm H., Simonen P., Kovanen P. T., Gylling H. & Öörni K. 2020, Arterioscler Thromb Vasc Biol. 40, 9 p. 2310–2321. doi: 10.1161/ATVBAHA.120.314329
Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths. Ruuth M., Nguyen S. D., Vihervaara T., Hilvo M., Laajala T. D., Kondadi P. K., Gisterå A., Lähteenmäki H., Kittilä T., Huusko J., Uusitupa M., Schwab U., Savolainen M. J., Sinisalo J., Lokki M. L., Nieminen M. S., Jula A., Perola M., Ylä-Herttula S., Rudel L., Öörni A., Baumann M., Baruch A., Laaksonen R., Ketelhuth D. F. J., Aittokallio T., Jauhiainen M., Käkelä R., Borén J., Williams K. J., Kovanen P. T., Öörni K. Jul 14, 2018, Eur Heart J. 39, 27, p. 2562–2573. doi: 10.1093/eurheartj/ehy319.
Extracellular lipids accumulate in human carotid arteries as distinct three-dimensional structures and have proinflammatory properties. Lehti S., Nguyen S. D., Belevich I., Vihinen H., Heikkilä H. M., Soliymani R., Käkelä R., Saksi J., Jauhiainen M., Grabowski G. A., Kummu O., Hörkkö S., Baumann M., Lindsberg P. J., Jokitalo E., Kovanen P. T. & Öörni K. Feb 2018, Am J Pathol. 188, 2, p. 525–538. doi: 10.1016/j.ajpath.2017.09.019.
p38δ MAPK: A novel regulator of NLRP3 inflammasome activation with increased expression in coronary atherogenesis. Rajamäki K., Mäyränpää M. I., Risco A., Tuimala J., Nurmi K., Cuenda A., Eklund K. K., Öörni K. & Kovanen P. T. Sep 2016 Arterioscler Thromb Vasc Biol. 36, 9. p. 1937-1946. doi: 10.1161/ATVBAHA.115.307312.
Spatial distributions of lipids in atherosclerosis of human coronary arteries studied by time-of-flight secondary ion mass spectrometry. Lehti S., Sjövall P., Käkelä R., Mäyränpää M. I.
Ramste M, Weldy C, Kundu S, Zhao Q, Li D, Brand K, Sharma D, Ramste A, Jagoda E, Ray J, Caceres RD, Galante J, Gschwind AR, Lahtinen N, Nguyen T, Amrute JM, Park CY, Kim JB, Kaikkonen MU, Stitziel NO, Steinmetz L, Kundaje A, Engreitz JM, Quertermous T. Enhancer-targeting CRISPR screens at coronary artery disease loci suggest shared mechanisms of disease risk. medRxiv [Preprint]. 2025 Sep 2:2025.08.28.25334684. doi: 10.1101/2025.08.28.25334684. PMID: 40950476; PMCID: PMC12424881. Under review
Tervi A*, Ramste M*, Abner E, Cheng P, Lane JM, Maher M, Valliere J, Lammi V, Strausz S, Riikonen J, Nguyen T, Martyn GE, Sheth MU, Xia F, Docampo ML, Gu W; FinnGen, Estonian Biobank research team; Esko T, Saxena R, Pirinen M, Palotie A, Ripatti S, Sinnott-Armstrong N, Daly M, Engreitz JM, Rabinovitch M, Heckman CA, Quertermous T, Jones SE, Ollila HM. Genetic and functional analysis of Raynaud’s syndrome implicates loci in vasculature and immunity. Cell Genom. 2024 Aug 9:100630. doi: 10.1016/j.xgen.2024.100630. Epub ahead of print. PMID: 39142284. *equal contribution
Räsänen M, Degerman D, Nissinen T A, Miinalainen I, Kerkelä R, Siltanen A, Backman JT, Mervaala E, Hulmi JJ, Kivelä R and Alitalo K. VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection. Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13144-13149. PMCID: PMC5135329.
Räsänen M, Sultan I, Paech J, Hemanthakumar KA, Yu W, He L, Tang J, Sun Y, Hlushchuk R, Huan X, Armstrong E, Khoma OZ, Mervaala E, Djonov V, Betsholtz C, Zhou B, Kivelä R, Alitalo K. VEGF-B Promotes Endocardium-Derived Coronary Vessel Development and Cardiac Regeneration. Circulation. 2021 Jan 5;143(1):65-77. Nov 18. PMID: 33203221.
Ramste M, Ritvos M, Häyrynen S, Kiiski JI, Niemi M, Sinisalo J. CYP2C19 loss-of-function alleles and use of omeprazole or esomeprazole increase the risk of cardiovascular outcomes in patients using clopidogrel. Clin Transl Sci. 2023 Aug 8. PMID: 37551775.
Kallström A, Holopainen I, Kambur O, Perola M, Salomaa V, Havulinna A, Ramste M*, Sinisalo Juha*. Divergent trends in the incidence and mortality of coronary events, especially in women. Evidence from Finland in 1996-2021. Ann Med. 2024 Dec;56(1):2424455. doi: 10.1080/07853890.2024.2424455. Epub 2024 Nov 26, *equal contribution
Sultan I, Ramste M, Peletier P, Hemanthakumar KA, Ramanujam D, Tirronen A, von Wright Y, Antila S, Saharinen P, Eklund L, Mervaala E, Ylä-Herttuala S, Engelhardt S, Kivelä R, Alitalo K. Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy. Circ Res. 2024 May 24;134(11):1465-1482. doi: 10.1161/CIRCRESAHA.123.324136. Epub 2024 Apr 24. PMID: 38655691.
Mannion AJ, Zhao H, Zhang Y, von Wright Y, Bergman O, Björck HM, Saharinen P, Holmgren L. The junctional mechanosensor AmotL2 regulates YAP promotor accessibility. BioRxiv, doi: https://doi.org/10.1101/2023.01.13.523596
Tuohinto K, DiMaio TA, Kiss EA, Laakkonen P, Saharinen P, Karnezis T, Lagunoff M and Ojala PM. KSHV infection of endothelial precursor cells with lymphatic characteristics as a novel model for translational Kaposi’s sarcoma studies. In press, PlosPathogen
Korhonen EA, Murtomäki A, Jha SK, Anisimov A, Pink A, Zhang Y, Stritt S, Liaqat I, Stanczuk L, Alderfer L, Sun Z, Kapiainen E, Singh A, Sultan I, Lantta A, Leppänen VM, Eklund L, He Y, Augustin HG, Vaahtomeri K, Saharinen P, Mäkinen T, Alitalo K. Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression. J Clin Invest. 132:e155478. 2022
Characterization of ANGPT2 mutations associated with primary lymphedema. Leppänen VM, Pascal Brouillard P, Korhonen EA, Sipilä T, Jha SK, Revencu N, Labarque V, Fastré E, Schlögel M, Ravoet M, Singer A, Luzzatto C, Angelone D, Crichiutti G, D’Elia A, Kuurne J, Elamaa H, Koh GY, Saharinen P, Vikkula M and Alitalo K. 2020, Sci Transl Med. 12(560):eaax8013.
Targeting β1-integrin inhibits vascular leakage in endotoxemia. Hakanpaa L, Kiss EA, Jacquemet G, Miinalainen I, Lerche M, Guzmán C, Mervaala E, Eklund L, Ivaska J, Saharinen P. 2018, Proc Natl Acad Sci (U S A). 115:E6467-E6476.
Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14-dependent Notch3 and β1-integrin activation. Pekkonen P, Alve S, Balistreri G, Gramolelli S, Tatti-Bugaeva O, Paatero I, Niiranen O, Tuohinto K, Perälä N, Taiwo A, Zinovkina N, Repo P, Icay K, Ivaska J, Saharinen P, Hautaniemi S, Lehti K, Ojala PM. 2018, Elife 7. pii: e32490.
Tie1 controls angiopoietin function in vascular remodeling and inflammation. Korhonen E, Lampinen A, Giri H, Anisimov A, Kim M, Allen B, Fang S, D’Amico G, Sipila T, Lohela M, Strandin T, Vaheri, Ylä-Herttuala S, Koh GY, McDonald DM, #Alitalo K and # Saharinen P. 2016, J Clin Invest. 126: 3495-3510. *#equal
Endothelial destabilization by angiopoietin-2 via integrin 1 activation. Hakanpaa L, Sipila T, Leppanen VM, Gautam P, Nurmi H, Jacquemet G, Eklund L, Ivaska J, Alitalo K, Saharinen P. Nature Commun. 6:5962, 2015.
Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery. Karaman S, Lehti S, Zhang C, Taskinen MR, Käkelä R, Mardinoglu A, Brorson H, Alitalo K, Kivelä R. FASEB Journal, 38(20):e70097, 2024
Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy. Sultan I, Ramste M, Peletier P, Hemanthakumar KA, Ramanujam D, Tirronen A, von Wright Y, Antila S, Saharinen P, Eklund L, Mervaala E, Ylä-Herttuala S, Engelhardt S, Kivelä R, Alitalo K. Circulation Research 134(11):1465-1482, 2024.
Serine synthesis pathway enzyme PHGDH is critical for muscle cell biomass, anabolic metabolism, and mTORC1 signaling. Mäntyselkä S, Kolari K, Baumert P, Ylä-Outinen L, Kuikka L, Lahtonen S, Permi P, Wackerhage H, Kalenius E, Kivelä R, Hulmi JJ. American Journal of Physiology – Endocrinology and Metabolism, 326(1):E73-E91, 2023.
PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets. Gizaw NY, Kallio P, Punger T, Gucciardo E, Haglund C, Böhling T, Lehti K, Sampo M, Alitalo K, Kivelä R. 2022, Proc Nat Acad Sci, 119(49):e2116220119.
Cardiovascular disease risk factors induce mesenchymal features and senescence in mouse cardiac endothelial cells. Hemanthakumar KA, Fang S, Anisimov A, Mäyränpää MI, Mervaala E, Kivelä R.2021, Elife 10:e62678.
VEGF-B promotes endocardium-derived coronary vessel development and cardiac regeneration. Räsänen M, Sultan I, Paech J, Hemanthakumar KA, Yu W, He L, Tang J, Sun Y, Hlushchuk R, HuanX, Armstrong E, Khoma OZ, Mervaala E, Djonov V, Betsholtz C, Zhou B, Kivelä R, Alitalo K. 2021, Circulation, 143: 65-77.
Flow-Induced Transcriptomic Remodeling of Endothelial Cells Derived From Human Induced Pluripotent Stem Cells. Helle E, Ampuja M, Antola L, Kivelä R. 2020, Front Physiol, 11:591450.
Angiogenesis and angiocrines regulating heart growth. Hemanthakumar KA, Kivelä R. 2020, Vasc Biol. 2(1): R93-R104.
Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2 -Mediated Paracrine Signaling. Kivelä R, Hemanthakumar KA, Vaparanta K, Robciuc M, Izumiya Y, Kidoya H, Takakura N, Peng X, Sawyer DB, Elenius K, Walsh K, Alitalo K. 2019, Circulation, 139:2570-2584.
Cardiomyocyte—Endothelial Cell Interactions in Cardiac Remodeling and Regeneration. Talman V, Kivelä R. 2018, Front Cardiovasc Med, 5:101.
Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle. Hulmi JJ, Nissinen TA, Räsänen M, Degerman J, Lautaoja JH, Hemanthakumar KA, Backman JT, Ritvos O, Silvennoinen M, Kivelä R. 2018, J Cachexia, Sarcopenia, Muscle, 9:417-432.
The transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre type regulation. Kivelä R, Salmela I, Nguyen YH, Petrova TV, Koistinen HA, Wiener Z, Alitalo K. 2016, Nat Commun, 7: 13124.
A closer look at adipose tissue lymphatics and their markers. Lackman MH, Subashi Y, Karaman S. Curr Opin Hematol. 2022 Feb 25
Interplay of vascular endothelial growth factor receptors in organ-specific vessel maintenance. Karaman S, Paavonsalo S, Heinolainen K, Lackman MH, Ranta A, Hemanthakumar KA, Kubota Y, Alitalo K. J Exp Med. 2022 Mar 7;219(3):e20210565
Capillary Rarefaction in Obesity and Metabolic Diseases-Organ-Specificity and Possible Mechanisms. Paavonsalo S, Hariharan S, Lackman MH, Karaman S. Cells. 2020 Dec 14;9(12):E2683.
Vascular endothelial growth factor signaling in development and disease. Karaman S, Leppänen VM, Alitalo K. Development. 20 Jul 2018;145(14). pii: dev151019
Development and plasticity of meningeal lymphatic vessels. Antila S, Karaman S, Nurmi H, Airavaara M, Voutilainen M, Mathivet T, Chilov D, Li Z, Koppinen T, Park JH, Fang S, Aspelund A, Saarma M, Eichmann A, Thomas JL, Alitalo K. J Exp Med. 15 Nov 2017. pii: jem.20170391
VEGFR3 modulates vascular permeability by controlling VEGF/VEGFR2 signaling. Heinolainen K, Karaman S, D’Amico G, Tammela T, Sormunen R, Eklund L, Alitalo K, Zarkada G. Circ Res. 28 Apr 2017;120(9):1414-1425.
Transgenic overexpression of VEGF-C induces weight gain and insulin resistance in mice. Karaman S, Hollmén M, Yoon SY, Alkan HF, Alitalo K, Wolfrum C, Detmar M. Sci Rep. 11 Aug 2016;6:31566
Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet. Karaman S, Hollmén M, Robciuc MR, Alitalo A, Nurmi H, Morf B, Buschle D, Alkan HF, Ochsenbein AM, Alitalo K, Wolfrum C, Detmar M. Mol Metab. 4 Dec 2014;4(2):93-105.
Schoofs H, Daubel N, Schnabellehner S, Grönloh MLB, Palacios Martínez S, Halme A, Marks AM, Jeansson M, Barcos S, Brakebusch C, Benedito R, Engelhardt B, Vestweber D, Gängel K, Linsenmeier F, Schürmann S, Saharinen P, van Buul JD, Friedrich O, Smith RS, Majda M, Mäkinen T. Dynamic cytoskeletal regulation of cell shape supports resilience of lymphatic endothelium. Nature in press (2025).
Petkova M, Kraft M, Stritt S, Martinez-Corral I, Ortsäter H, Vanlandewijck M, Jakic B, Baselga E, Castillo SD, Graupera M, Betsholtz C, Mäkinen T. Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation. J Exp Med Apr 3;220(4):e20220741. doi: 10.1084/jem.20220741 (2023).
Hernández Vásquez MN, Ulvmar MH, González-Loyola A, Kritikos I, Sun Y, He L, Halin C, Petrova TV, Mäkinen T. Transcription factor FOXP2 is a flow-induced regulator of collecting lymphatic vessels. EMBO J 40(12):e107192. doi: 10.15252/embj.2020107192 (2021).
Frye M, Stritt S, Ortsäter H, Hernandez-Vasquez M, Kaakinen M, Vicente A, Wiseman J, Eklund L, Martinez-Torrecuadrada JL, Vestweber D, Mäkinen T. EphrinB2-EPHB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity. eLife 9:e57732 (2020).
Martinez-Corral I, Zhang Y, Petkova M, Ortsäter H, Sjöberg S, Diez SC, Brouillard P, Libbrecht L, Graupera M, Alitalo K, Boon L, Vikkula M, Mäkinen T. Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation. Nat Commun 11:2869 doi: 10.1038/s41467-020-16496-y (2020).
Frye M, Taddei A, Dierkes C, Martinez-Corral I, Fielden M, Ortsäter H, Kazenwadel J, Calado DP, Ostergaard P, Salminen M, He L, Harvey N, Kiefer F, Mäkinen T. Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. Nat Commun, 9:1511 doi: 10.1038/s41467-018-03959-6 (2018).
Zhang Y, Ulvmar MH, Stanczuk L, Martinez-Corral I, Frye M, Alitalo, K, Mäkinen T. Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms. Nat Commun 9:1296 doi: 10.1038/s41467-018-03692-0 (2018).
Martinez-Corral I, Ulvmar MH, Stanczuk L, Tatin F, Kizhatil K, John SWM, Alitalo K, Ortega S, Makinen T. Non-venous origin of dermal lymphatic vasculature. Circ Res 116:1649-1654 (2015).
Stanczuk L, Martinez-Corral I, Ulvmar MH, Zhang Y, Lavina B, Fruttiger M, Adams RH, Saur D, Betsholtz C, Ortega S, Alitalo K, Graupera M, Mäkinen T. cKit lineage hemogenic endothelium-derived cells contribute to mesenteric lymphatic vessels. Cell Rep 10:1708-1721 (2015).
Tatin F, Taddei A, Weston A, Fuchs E, Devenport D, Tissir F, Makinen T. Planar cell polarity protein Celsr1 regulates endothelial adherens junctions and directed cell rearrangements during lymphatic valve morphogenesis. Dev Cell 15:31-44 (2013).
Lutter S, Xie S, Tatin F, Makinen T. Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation. J Cell Biol 197:837-49 (2012).
Bazigou E, Lyons OTA, Smith A, Venn GE, Cope C, Brown NA, Makinen T. Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice. J Clin Invest 121:2984-92 (2011).
Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, Adams R, Muro A, Sheppard D, Makinen T. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell 17:175-186 (2009).