The aim of our research is to establish novel therapy modalities based on knowledge of the biology of vascular endothelial growth factors (VEGFs), angiopoietins (Ang), and the growth of blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis). Current cardiovascular and cancer therapies are often insufficient, unsuccessful or not suitable for all patients, thus novel therapies are urgently needed. Inhibition of vessel growth is already used in the clinics, but with limited success. On the other hand, stimulation of the growth of blood vessels, angiogenesis, and of arteriogenesis, the growth of (collateral) arteries, has been unsuccessfully tried for the treatment of tissue ischemia.
We explore the functions and the translational potential of the vascular growth factors and receptors that we have discovered. Our results have suggested therapeutic utility in a number of human diseases. In our studies, we use molecular genetic models and functional genomics, single-cell transcriptomics, proteomics and metabolomics, viral vectors for gene delivery and biologicals that block growth factor-receptor interactions. Using this technology platform, we are well suited and networked for new discoveries with the aim to advance current therapy of cardiovascular diseases and several other human diseases. Three of our previous concepts have already been translated to clinical development and we aim to provide additional therapeutic modalities.
Our work on endothelial growth factors and our new discoveries should provide the possibility of exploring additional treatments for human diseases in which the vasculature is an essential participant.
Members of the VEGF family, comprising five mammalian proteins, are major regulators of blood and lymphatic vessel development and growth. VEGFs stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells.
In physiological and pathological angiogenesis, lack of sufficient oxygen induces the production of VEGF, which stimulates vessel growth mainly via VEGFR-2, whereas VEGFR-1 serves mostly as a decoy receptor without effective signal transduction. Although antibodies that block VEGF have been successfully used in tumor therapy, attempts to use VEGF for proangiogenic therapy in tissue ischemia have been hampered by VEGF-induced vascular leakage and growth of abnormal vessels.
VEGF-B has remained rather enigmatic since its discovery more than 20 years ago. However, we have shown that VEGF-B provides protection from myocardial infarction by expanding the coronary vasculature and cardiac muscle mass. Furthermore, VEGF-B expression is decreased in failing hearts. It seems that VEGF-B administration provides a unique possibility to remodel the myocardial vasculature for better blood flow in the heart and in adipose tissue. Our experiments indicate that VEGF-B can also improve glucose and insulin tolerance in obese mice (Robciuc et al., 2016; Räsänen et al. 2020).
In adults, the VEGF-C and VEGF-D receptor, VEGFR-3, is expressed primarily in the lymphatic vasculature, where it acts as a regulator of lymphatic vessel growth. VEGFR-3 is also expressed in growing blood vessels. In 2015, we discovered a meningeal lymphatic vessel system around the brain (Aspelund et al. 2015). We are currently studying the possible functions of VEGF-C/VEGFR-3 in cerebrovascular dynamics, fluid drainage and cellular trafficking in mouse models of Alzheimer’s disease and of multiple sclerosis. The meningeal lymphatics could be involved in a number of neurodegenerative and neuroinflammatory diseases of considerable socioeconomic burden. Angiopoietins (Ang1, Ang2, Ang4) are critical for vascular stabilization after angiogenesis (Saharinen et al., 2017a, b). We have recently shown how the angiopoietin receptor complex Tie1/Tie2 regulates vessel leakage in inflammation (Korhonen et al., 2017), that blocking of Ang2 attenuates neuroinflammation (Li et al., 2020) and that Ang2 mutations are associated with human lymphedema (Leppänen et al., 2020). The unique role of the Ang-Tie signaling pathway in vascular stability suggests that it could serve as a target of therapeutic intervention in diseases in which the vascular integrity is compromised.
A Dural Lymphatic Vascular System that Drains Brain Interstitial Fluid and Macromolecules. Aspelund, A., Antila, S., Proulx, S. T., Karlsen, T. V., Karaman, S., Detmar, M., Wiig, H. & Alitalo K., 25 Jun 2015, J Exp Med. 212, 7, p. 991-999
Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2-Mediated Paracrine Signaling. Kivelä, R., Hemanthakumar, K. A., Vaparanta, K., Robciuc, M., Izumiya, Y., Kidoya, H., Takakura, N., Peng, X., Sawyer, D. B., Elenius, K., Walsh, K. & Alitalo, K., 28 May 2019, Circulation. 139, 22, p. 2570-2584.
VEGF-B-induced Vascular Growth Leads to Metabolic Reprogramming and Ischemia Resistance in the Heart. Kivelä, M. R., Bry, M., Robciuc, M. R., Räsänen, M., Taavitsainen, M., Silvola, J. M. U., Saraste, A., Hulmi, J. J., Anisimov, A., Mayranpaa, M. I., Lindeman, J. H., Eklund, L., Hellberg, S., Hlushchuk, R., Zhuang, Z. W., Simons, M., Djonov, V., Knuuti, J., Mervaala, E. & Alitalo, K., Mar 2014, EMBO molecular medicine. 6, 3, p. 307-321
Tie1 Controls Angiopoietin Function in Vascular Remodeling and Inflammation. Korhonen, E. A., Lampinen, A., Giri, H., Anisimov, A., Kim, M., Allen, B., Fang, S., D’Amico, G., Sipila, T. J., Lohela, M., Strandin, T., Vaheri, A., Ylä-Herttuala, S., Koh, G. Y., McDonald, D. M., Alitalo, K. & Saharinen, P., 1 Sep 2016, J Clin Invest. 126, 9, p. 3495-3510
Characterization of ANGPT2 Mutations Associated with Primary Lymphedema. Leppänen, V-M., Brouillard, P., Korhonen, E. A., Sipilä, T., Jha, S.K., 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, G. Y., Saharinen, P., Vikkula, M. & Alitalo, K., 9 Sep 2020, Sci Transl Med 12, 560, p. eaax8013
Angiopoietin-2 Blockade Ameliorates Autoimmune Neuroinflammation by Inhibiting Leukocyte Recruitment into the CNS. Li, Z., Korhonen, E. A., Merlini, A., Strauss, J., Wihuri, E., Nurmi, H., Antila, S., Paech, J., Deutsch, U., Engelhardt, B., Chintharlapalli, S., Koh, G. Y., Flügel, A. & Alitalo, K., 1 Apr 2020, Journal of Clinical Investigation. 130, 4, p. 1977-1990
VEGFB/VEGFR1-Induced Expansion of Adipose Vasculature Counteracts Obesity and Related Metabolic Complications. Robciuc, M. R., Kivelä, R., Williams, I. M., de Boer, J. F., van Dijk, T. H., Elamaa, H., Tigistu-Sahle, F., Molotkov, D., Leppänen, V-M., Käkelä, R., Eklund, L., Wasserman, D. H., Groen, A. K. & Alitalo, K., 12 Apr 2016, Cell Metabolism. 23, 4, p. 712-724
VEGF-B Promotes Endocardium-Derived Coronary Vessel Development and Cardiac Regeneration. Räsänen, M., Sultan, I., Paech, J., Hemanthakumar, K. A., Yu, W., He, L., Tang, J., Sun, Y., Hlushchuk, R., Huang, X., Armstrong, E., Khoma, O. Z., Mervaala, E., Djonov, V., Betsholtz, C., Zhou, B., Kivelä, R. & Alitalo, K., 18 Nov 2020, Circulation. doi: 10.1161/CIRCULATIONAHA.120.050635. Online ahead of print
Therapeutic Targeting of the Angiopoietin-TIE Pathway. Saharinen, P., Eklund, L. & Alitalo, K., 16 Sep 2017, Nat Rev Drug Discov. 16, 9, p. 635-661
SnapShot: Angiopoietins and Their Functions. Saharinen, P., Leppänen, V-M. & Alitalo, K., 19 Oct 2017, Cell. 171, 3, p. 724-724.e1
Andrey Anisimov, Ph.D., Adjunct Professor, Senior Research Scientist
Salli Antila, M.D., Ph.D. Student
Shentong Fang, P.hD., Postdoctoral Researcher
Sawan Jha, Ph.D., Postdoctoral Researcher
Veli-Matti Leppänen, P.hD., Adjunct Professor, Senior Research Scientist
Ibrahim Sultan, Ph.D. Student
Aino Tedeton, Ph.D., Postdoctoral Researcher