Lars Jakobsson Group
Vascular morphogenesis and function in health and disease
– Molecular and multi-cellular dynamics
Dysfunction and mispatterning of the blood and lymphatic vasculature 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 vasculature depend on the interplay between its major units; the endothelial cells (ECs), the supportive mural cells (pericytes and smooth muscle cells), and their shared basement membrane (BM).
We study the molecular and cellular processes whereby the blood vasculature adapts its size, architecture and function to optimally meet the changing demands from tissue with the aim to understand and prevent malformation and malfunction in disease.
We have previously revealed and described extensive cellular dynamics during blood vessel formation (angiogenesis) (Jakobsson et al, Nat Cell Biol, 2010).
Technology and resources
- We utilise 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
- Tissue-clearing techniques
- Light-sheet microscopy
- Large scale proteomics
- Mouse embryonic stem cell models
Multi-cellular interplay in regulation of vascular patterning and function
The interaction of mural and endothelial cells is known to be required for proper vascular function. We are currently characterizing this cellular interplay and its impact on vascular remodelling and function in various genetic models by live imaging techniques, ex vivo and in vivo.
Mechanisms of vascular malformation
The endothelial specific TGFß/BMP co-receptor Endoglin is required for vascular development and function. Mutations in this gene cause the human disease HHT, also known as the Osler Weber Rendu syndrome, characterised by vascular abnormalities and ruptures. We are currently studying the precise mechanisms and roles of Endoglin in development and function of the vasculature of the Central Nervous System (CNS). Our disease models, including genetic GOF, LOF and conditional reporters, provide unique information on vascular malformation. We are now investigating new targets to treat HHT1.
Visualizing the 3D architecture of the brain vasculature.
Drug-induced endothelial specific endogenous fluorescence allows for 3D rendering of the brain vasculature. The tissue has been optically cleared and imaged using our multiphoton confocal system.
The Basement membrane – facilitating structured signalling
Endothelial cells and pericytes rest on a matrix of several proteins that interconnect to form the basement membrane (BM). Laminins are key components in the formation of the vascular BM. Alterations in the BM composition is commonly seen in tumours. Using conditional alleles we study the role of Laminins on vascular function, tumour growth and metastasis.
The lymphatic vasculature
Insufficient drainage of tissue liquid causes lymphedema with severe impact on a large group of patients. These conditions may occur as a consequence of defective valves or abnormal mural cell coverage of the lymphatic vasculature. Extracellular proteins and their integrin receptors have been shown to affect the formation of the valves. Here we are investigating the role of Laminins on valve formation and architecture.
In vivo imaging of cellular dynamics in vascular morphogenesis
We utilise in vivo, single and multiphoton confocal imaging of several organs (eye, ear and Cremaster) to describe the dynamics of vascular morphogenesis, permeability and function.
Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity.
Yixin Wang, Yi Jin, Maarja Andaloussi Mäe, Yang Zhang, Henrik Ortsäter, Christer Betsholtz, Taija Mäkinen, Lars Jakobsson, Development 2017, doi: 10.1242/dev.147967
Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling.
Nat. Cell Biol. 2017 Jun;19(6):639-652
Läs hela artikeln.
Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues.
Nat. Cell Biol. 2017 Jun;19(6):653-665
Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D-PDGFRβ signaling.
J. Cell. Sci. 2017 04;130(8):1365-1378
RhoA inhibits neural differentiation in murine stem cells through multiple mechanisms.
Sci Signal 2016 Jul;9(438):ra76
Transforming growth factor β family members in regulation of vascular function: in the light of vascular conditional knockouts.
Exp. Cell Res. 2013 May;319(9):1264-70
The dynamics of developmental and tumor angiogenesis-a comparison.
Cancers (Basel) 2012 Apr;4(2):400-19
VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling.
Nat. Cell Biol. 2011 Sep;13(10):1202-13
Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting.
Nat. Cell Biol. 2010 Oct;12(10):943-53
Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization.
Blood 2008 Nov;112(9):3638-49
Laminin deposition is dispensable for vasculogenesis but regulates blood vessel diameter independent of flow.
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.
J. Biol. Chem. 2008 May;283(20):13905-12
Building blood vessels--stem cell models in vascular biology.
J. Cell Biol. 2007 Jun;177(5):751-5
Angiomotin regulates endothelial cell migration during embryonic angiogenesis.
Genes Dev. 2007 Aug;21(16):2055-68
Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis.
Dev. Cell 2006 May;10(5):625-34
We are very grateful for the financial support from:
- The Swedish Research Council (Vetenskapsrådet)
- The Swedish Cancer Society (Cancerfonden)
- William K. Bowes, Jr. Foundation
- The Cardiovascular Programme (KI and the Stockholm County Council)
- The Strategic Programme for Neuroscience, (Stratneuro, KI)
- Karolinska Institutet
- Jeanssons Stiftelse
- Magnus Bergvalls stiftelser
- Åke Wibers stiftelse
Anne-Claire Duchez - Associated
Lars Jakobsson - Assistant professor
Yi Jin - Postdoc
Yixin Wang - PhD student
David Kaluza - Postdoc, EMBO Fellow.
Leonie Schoch - Erasmus student
Zacharias Iredahl - Biomed/Medical student
Oguzhan Kaya – Erasmus student
Mikhail Burmakin – Postdoc, Lab manager