The inner lining of blood and lymphatic vessels is composed of endothelial cells, which are in a key position to maintain vessel function. Altogether, endothelial cells in our bodies form a semipermeable barrier estimated to cover an area comparable to that of six tennis courts. Malfunction or impaired integrity of the endothelial cell layer leads to fluid accumulation in tissues. Fluid leakage can impair blood perfusion and cause edema in various common diseases, such as sepsis. However, stopping vessel leakage remains a challenge in many diseases.
Comprehensive understanding of what causes vessel leakiness and how leaky vessels can be repaired, is incomplete. By studying the fundamental principles of how blood and lymphatic vessel stability is maintained, we aim to understand the mechanisms that cause vessel leakiness or malfunction in inflammatory diseases. Understanding of these mechanisms is important for translational research targeted to improve vascular stability and function in various diseases.
Pathological vessel leakage
The blood and lymphatic vascular systems regulate tissue homeostasis by controlling tissue fluid balance, inflammation and immune surveillance. The integrity of blood vessels is paramount for proper functioning of the vascular system. Impaired vascular integrity is associated with acute and chronic inflammation and pathological vessel growth in many common, but difficult-to-treat diseases, including cardiovascular, inflammatory, metabolic and even neurological disorders (Nat Rev Drug Disc, 2017, review).
Molecular regulation of endothelial barriers
Endothelial cells form organotypic vascular barriers and maintain vessel stability via coordinated signaling induced by growth factors, cytokines and cell adhesive- and mechanical forces. Our group has discovered mechanisms of how the endothelial Angiopoietin (Angpt)-Tie growth factor receptor signaling pathway leads to vascular leakage (J Clin Invest, 2016). Recently, our group has discovered mechanisms by which Angpt-2 destabilizes endothelial monolayers via binding to beta1-integrin. Moreover, we showed that by blocking beta1-integrin with antibodies or decreasing its expression levels via heterozygous endothelial-specific gene deletion, vascular leakage was halted in a sepsis model and this improved cardiac function (Nat Commun, 2015; PNAS, 2018). Furthermore, we identified a novel cellular pathway regulated by Tensin1-positive fibrillar adhesions that increased endothelial cellular tension, leading to an increase of endothelial permeability (PNAS, 2018).
We use inducible tissue type-specific gene deletions and various disease models, combined with light-sheet and intravital multiphoton microscopy and micro-computed tomography imaging, single-cell RNA sequencing, cell culture models, as well as biochemical and structural analyses to understand the mechanism of vascular stability and leakage regulation. We also collaborate with clinician scientists to correlate our preclinical results and findings from human diseases (Plos One, 2016; Clin Genitourinary Cancer, 2017).
Our main research areas include:
(1) The role of adhesive forces in vascular stability and permeability
(2) Adhesion receptor and growth factor receptor signalling in inflammation
(3) Molecular and atomic level understanding of endothelial permeability regulation
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.
Receptor Tyrosine Kinase Signaling Networks Define Sensitivity to ERBB Inhibition and Stratify Kras-Mutant Lung Cancer. Talwelkar SS, Nagaraj AS, Devlin JR, Hemmes A, Potdar S, Kiss EA, Saharinen P, Salmenkivi K, Mäyränpää MI, Wennerberg K, Verschuren EW. 2019, Mol Cancer Ther, 18: 1863-1874.
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.
Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization. Leppanen VM, Saharinen P and Alitalo, K. 2017, Proc Natl Acad Sci (USA). 114: 4376-4381.
Angiopoietin-Tie signaling in the cardiovascular and lymphatic systems. Eklund L, Kangas J, Saharinen P. 2017, Clinical Science. 1:87-103.
Therapeutic targeting of the angiopoietin-Tie pathway. Saharinen P, Eklund L, Alitalo K. 2017, Nat Rev Drug Disc. 16:635-661.
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
Association of Angiopoietin-2 and Ki-67 Expression with Vascular Density and Sunitinib Response in Metastatic Renal Cell Carcinoma. Rautiola J*, Lampinen A*, Mirtti T, Ristimäki A, Joensuu H, Bono P, Saharinen P. 2016, PLoS One. 11(4):e0153745. *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.
Elina A. Kiss, Postdoctoral Researcher
Anne Pink, Postdoctoral Researcher
Kumar Ponna, Postdoctoral Researcher
Niina Santio, Postdoctoral Researcher
Abhinandan Venkatesha Murthy, Postdoctoral Researcher
Keerthana Ganesh, Doctoral student
Tuomas Sipilä, Doctoral student
Ylva von Wright, Doctoral student
Aleksi Halme, Master’s student
Pihla Kaipainen, Master’s student
Seyedehshima Naddafi, Master’s student
Laura Seitakari, Med. student
Heidi Toivonen, Master’s student
Shadi Jansouz, Laboratory coordinator
Riina Lampela, Laboratory coordinator
Laura Hakanpää, completed PhD thesis in the group
Anita Lampinen, completed PhD thesis in the group
Eric Coles, completed M.Sc. thesis in the group
Prson Gautam, completed M.Sc. thesis in the group
Aleksi Halme, completed B.Sc. thesis in the group
Ciia Kohonen, completed B.Sc. thesis in the group
Ella Tuominen, completed B.Sc. thesis in the group
Noora Nurminen, completed B.Sc. thesis in the group
Lavinia van der Sande, Kaho Sint Leuven, Belgium, completed B.Sc. thesis in the group
Julie Drighe, Kaho Sint Leuven, Belgium, completed B.Sc. thesis in the group
Rita Teixeira, Ecola Superior de Saude, Porto, Portugal, Erasmus student
Joel Noutere, undergraduate student
Riina Haajanen, undergraduate student
Elisa Ritola, undergraduate student
Hanna Vihervaara, undergraduate student
Salla Välipakka, undergraduate student
Janina Allekotte, undergraduate student
Anni Ojansivu, undergraduate student
Seija Tillanen, Senior Laboratory Analyst
Kirsi Mänttäri, Laboratory technician
Janine Weis, M.Sc.