Lars Jakobsson group
Vascular morphogenesis and function in health and disease
Dysfunction and mispatterning of the blood and lymphatic vasculatures are central in the progression or development of several diseases such as cancer, lymphedema, diabetic retinopathy, trauma, stroke complications, hereditary haemorrhagic telangiectasia (HHT) and ischemic heart disease.
The formation and function of the vascular system of arteries, capillaries and veins rely on properties of the components of the vascular wall; the endothelial cells (ECs), the supportive mural cells (pericytes and smooth muscle cells), astrocytes (in the CNS) and their shared basement membrane (BM).
We study molecular and cellular processes whereby the blood and lymphatic vasculatures adapt their size, architecture, and function to optimally meet the changing demands from tissue. The aim is to utilize the acquired knowledge to develop means to prevent vascular malformation and malfunction in disease. The research field is directly relevant to a vast number of human pathologies, including vascular anomalies, heart disease, stroke, diabetes complications, cancer, lymphedema, and inflammatory diseases.
Technology and resources
- Mice with inducible and cell specific genetic gain- and loss- of function in combination with a repertoire of conditional and cell specific reporters allowing for lineage tracing, clonal analysis and cell sorting.
- Multi-photon intravital imaging
- Confocal live cell imaging
- Fluidics and in vitro experimentation
- Tissue-clearing techniques
- Light-sheet microscopy
- Large scale proteomics
- Mouse embryonic stem cell models
- AAV-mediated gene modulation
Our work has exposed fundamental principles of how endothelial and mural cells organise into functional arteries, capillaries and veins through sprouting angiogenesis. We now know that this involves extensive cellular dynamics instructed by signalling via serum- and tissue- derived cytokines, inter-endothelial communication as well as flow-mediated shear forces. We deepen the knowledge on the interplay between, and impact of, several signalling cascades that are central for creation and maintenance of vessel architecture and function. By applying state-of-the-art basic science to resolve clinical problems, we aim to advance treatment of several vascular-related diseases. Please see our publications for details on previous contributions.
Mechanisms of vascular malformation
Endoglin is an EC expressed coreceptor for bone morphogenetic protein-9/10, a ligand found in serum. Loss-of-function mutations in the endoglin gene cause the human disease HHT1, also known as the Osler Weber Rendu syndrome, characterised by vascular abnormalities such as arterio-venous malformations that lead to bleeding, anemia and high output heart failure. Recent advances have provided promising treatments but with relapse and side effects. We have shown that ECs require endoglin in order to respond correctly to blood flow. Without endoglin – such as in the disease HHT1 – ECs cannot control their size, migratory behaviour or proliferation in accordance with flow. We continue to dissect mechanisms of this phenomena utilizing unique genetic disease models applying tools mentioned above. We are now investigating new targets to treat HHT1.
The Basement membrane – facilitating structured signalling
ECs and pericytes rest on a matrix of several proteins that interconnect to form the basement membrane (BM). Laminins are key components of the vascular BM that transmits information to ECs mainly via the integrins. Alterations in the BM composition and organisation is commonly seen in tumours and vascular eye disease. Using conditional alleles, we study the role of laminins in establishment and function of the vasculature in physiology and pathology, such as during tumour growth and inflammation.
The vasculature in eye disease – a complete picture
Each compartment of the eye is supported by its individual specialised blood vasculature. These individual vascular beds are in turn involved in specific forms of eye disease. To extract deep information on structural properties of these vasculatures and their interplay in development, health and disease we refine and apply high resolution microscopy, including light-sheet fluorescence microscopy on intact murine eyes. These technologies allow for reconstruction of the whole eye in three dimensions, see 3D rendering below.
Patterning and transformation of the lymphatic vasculature
The lymphatic vasculature drains fluid from tissue, via its blind-ended capillaries through collecting vessels to blood circulation. We have shown that recruitment of smooth muscle cells to collecting vessels relies on the secretion of PDGFB from lymphatic endothelial cells, in turn required for their contractile function. The importance of lymphatic vascular functionality is highlighted by extensive oedema in specific genetic diseases affecting lymph valves, as well as following lymph node removal in breast cancer.
Here we study specific genes and signalling cascades that have been associated with rare transitions of the lymphatic endothelium into cancers. Through careful analysis of the progression in experimental models we hope to find key features that can be modulated as part of future therapy.
Anatomy of the complete mouse eye vasculature explored by light-sheet fluorescence microscopy exposes subvascular-specific remodeling in development and pathology.
Krimpenfort LT, Garcia-Collado M, van Leeuwen T, Locri F, Luik AL, Queiro-Palou A, Kanatani S, André H, Uhlén P, Jakobsson L
Exp Eye Res 2023 Oct;():109674
Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signaling.
Tual-Chalot S, Garcia-Collado M, Redgrave RE, Singh E, Davison B, Park C, Lin H, Luli S, Jin Y, Wang Y, Lawrie A, Jakobsson L, Arthur HM
Circ Res 2020 Jan;126(2):243-257
Characterization of multi-cellular dynamics of angiogenesis and vascular remodelling by intravital imaging of the wounded mouse cornea.
Wang Y, Jin Y, Laviña B, Jakobsson L
Sci Rep 2018 Jul;8(1):10672
Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity.
Wang Y, Jin Y, Mäe MA, Zhang Y, Ortsäter H, Betsholtz C, et al
Development 2017 10;144(19):3590-3601
Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling.
Jin Y, Muhl L, Burmakin M, Wang Y, Duchez AC, Betsholtz C, et al
Nat. Cell Biol. 2017 Jun;19(6):639-652
Read the whole article.
Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues.
Sugden WW, Meissner R, Aegerter-Wilmsen T, Tsaryk R, Leonard EV, Bussmann J, et al
Nat. Cell Biol. 2017 Jun;19(6):653-665
Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D-PDGFRβ signaling.
Muhl L, Folestad EB, Gladh H, Wang Y, Moessinger C, Jakobsson L, et al
J. Cell. Sci. 2017 04;130(8):1365-1378
RhoA inhibits neural differentiation in murine stem cells through multiple mechanisms.
Yang J, Wu C, Stefanescu I, Jakobsson L, Chervoneva I, Horowitz A
Sci Signal 2016 07;9(438):ra76
TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis.
Pang M, Georgoudaki A, Lambut L, Johansson J, Tabor V, Hagikura K, et al
Oncogene 2016 Feb;35(6):748-60
Transforming growth factor β family members in regulation of vascular function: in the light of vascular conditional knockouts.
Jakobsson L, van Meeteren L
Exp. Cell Res. 2013 May;319(9):1264-70
The sphingosine-1-phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE-cadherin and VEGFR2.
Gaengel K, Niaudet C, Hagikura K, Laviña B, Siemsen B, Muhl L, et al
Dev. Cell 2012 Sep;23(3):587-99
The dynamics of developmental and tumor angiogenesis-a comparison.
Jin Y, Jakobsson L
Cancers (Basel) 2012 Apr;4(2):400-19
VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling.
Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, et al
Nat. Cell Biol. 2011 Sep;13(10):1202-13
Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting.
Jakobsson L, Franco C, Bentley K, Collins R, Ponsioen B, Aspalter I, et al
Nat. Cell Biol. 2010 Oct;12(10):943-53
Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization.
Kawamura H, Li X, Goishi K, van Meeteren LA, Jakobsson L, Cébe-Suarez S, et al
Blood 2008 Nov;112(9):3638-49
Laminin deposition is dispensable for vasculogenesis but regulates blood vessel diameter independent of flow.
Jakobsson L, Domogatskaya A, Tryggvason K, Edgar D, Claesson-Welsh L
FASEB J. 2008 May;22(5):1530-9
Endothelial cell migration in stable gradients of vascular endothelial growth factor A and fibroblast growth factor 2: effects on chemotaxis and chemokinesis.
Barkefors I, Le Jan S, Jakobsson L, Hejll E, Carlson G, Johansson H, et al
J. Biol. Chem. 2008 May;283(20):13905-12
Building blood vessels--stem cell models in vascular biology.
Jakobsson L, Kreuger J, Claesson-Welsh L
J. Cell Biol. 2007 Jun;177(5):751-5
Angiomotin regulates endothelial cell migration during embryonic angiogenesis.
Aase K, Ernkvist M, Ebarasi L, Jakobsson L, Majumdar A, Yi C, et al
Genes Dev. 2007 Aug;21(16):2055-68
Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis.
Jakobsson L, Kreuger J, Holmborn K, Lundin L, Eriksson I, Kjellén L, et al
Dev. Cell 2006 May;10(5):625-34
The lab is part of V.A. Cure - a European MSCA-ITN network.
We are very grateful for the financial support from:
- Ögonfonden/The eye foundation
- The Cardiovascular Programme (KI and the Stockholm County Council)
- The European Commission
- Jeanssons Stiftelse
- Karolinska Institutet
- Magnus Bergvalls stiftelser
- Petrus och Augusta Hedlunds Stiftelse
- Ruth och Nils-Erik Stenbäcks stiftelse
- The Brain Foundation
- The Heart and Lung Foundation
- The Strategic Programme for Neuroscience, (Stratneuro, KI)
- The Swedish Cancer Society (Cancerfonden)
- The Swedish Medical Society
- The Swedish Research Council (Vetenskapsrådet)
- William K. Bowes, Jr. Foundation
- Åke Wibergs stiftelse
- Nicole Laszlo - Medical student
- Stephanie Preuss - Master student
- Yixin Wang - Postdoc
- Yi Jin - Postdoc
- Anne-Claire Duches - Postdoc
- David Kaluza - Postdoc - EMBO Fellow
- Leonie Schoch - Erasmus student
- Zacharias Iredahl - Biomed/Medical student
- Oguzhan Kaya – Erasmus student
- Mikhail Burmakin – Postdoc, Lab manager
Jakobsson lab is looking for postdocs, please contact Lars.Jakobsson@ki.se to hear more about available funded positions.