Daniel Nyqvist Group
The common goal of our research is to identify and characterize signaling pathways that play a critical role for vascular development and function in health and disease. We are interested in mechanisms that regulate both vessel growth and barrier function in normal and disease conditions, primarily cancer and diabetes.
Wnt/β-catenin signaling in blood vessel growth and function
Wnt signaling controls numerous cellular mechanisms throughout development and adult life, and underlies a wide range of human pathologies. Wnts comprise a large family of secreted glycolipoproteins that signals via Frizzled and LRP receptors. In the canonical pathway, the binding of Wnt to its receptors blocks phosphorylation and degradation of β-catenin, and enables β-catenin to accumulate and translocate to the nucleus to activate gene transcription. In addition to its role as a transcription factor, β-catenin function as a component of the adherens junctions and thus provides a link between cell adhesion and signaling. Genetic disorders have revealed a critical role for canonical Wnt/β-catenin signaling for the development of the retinal vasculature in humans, while current research has showed that Wnt/β-catenin signaling is vital for CNS angiogenesis and blood-brain barrier (BBB) formation.
Our research is focused on elucidating the role of endothelial Wnt/β-catenin signaling in vessel growth and barrier function. We have previously found that endothelial Wnt/β-catenin is an important player during embryonic vascular development by modulating vascular remodeling and up-regulating Dll4/Notch signaling. We are now investigating the role of endothelial Wnt/β-catenin signaling during post-natal vascular developmental and tumor angiogenesis.
VEGF-B signaling in pancreatic β-cell lipid uptake and physiology
The vascular endothelial growth factor (VEGF)-B was recently discovered to control the transport of fatty acids over the endothelium. Paracrine VEGF-B signaling regulates the expression of fatty acid transporters (FATPs) on endothelial cells and thereby trans-endothelial lipid transport. VEGF-B deficient mice have reduced expression of endothelial FATPs and reduced peripheral lipid uptake. We have recently found that blocking VEGF-B signaling in models of type 2 diabetes dramatically reduces lipid uptake to peripheral tissues, improves insulin resistance and glucose tolerance, and protects against development of type 2 diabetes. Interestingly, also pancreatic morphology and triglyceride content were significantly improved after targeting the VEGF-B pathway.
Extensive research has identified increased and dysregulated lipid handling as an early hallmark of β-cell dysfunction and failure during development of type 2 diabetes. Our goal with this project is to elucidate the role of paracrine VEGF-B signaling for pancreatic islet and β-cell lipid handling in normal and type 2 diabetic conditions.
Dynamic imaging of angiogenesis and tumor angiogenesis
Blood vessel growth and barrier function are highly dynamic processes. To provide a better understanding of these processes and their underlying mechanisms we are currently developing methods for live cell and intravital confocal imaging. We have previously established a novel model for in vivo imaging of pancreatic islets transplanted to the anterior chamber of the eye (AC). This model facilitates noninvasive and repetitive high-resolution imaging of tissue implanted in the AC using the cornea as a natural body window. We are currently adapting this model to facilitate high-resolution imaging of angiogenesis and tumor angiogenesis in 4 dimensions (4D). To aid the visualization of different cell types and signaling process we take advantages of a variety of fluorescent reporters models.
|Marta Alabrudzinska||Research assistant|
|Chenfei Ning||Research assistant on study grant|
|Daniel Nyqvist||Assistant professor|
Aravindh Subramani - MSc
We are very grateful to have received support from:
- The Swedish Research Council (VR)
- Swedish Society for Medical Research (SSMF)
- The Cancer Society (Cancerfonden)
- The Diabetes association (Diabetesfonden)
- Diabetes Wellness Foundation
- Karolinska Institutet
- Åke Wibergs Stiftelse
- Magnus Bergvalls Stiftelse
- Jeanssons Stiftelser
- O.E och Edla Johanssons Vetenskapliga Stiftelse
- Stiftelsen Sigurd och Elsa Goljes Minne
- Eva och Oscar Ahréns Stiftelse
The alternative splicing factor Nova2 regulates vascular development and lumen formation.
Nat Commun 2015 Oct;6():8479
Sox17 is indispensable for acquisition and maintenance of arterial identity.
Nat Commun 2013 ;4():2609
Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes.
Nature 2012 Oct;490(7420):426-30
Donor islet endothelial cells in pancreatic islet revascularization.
Diabetes 2011 Oct;60(10):2571-7
The Wnt/beta-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling.
Dev. Cell 2010 Jun;18(6):938-49
Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis.
Dev. Cell 2009 Jan;16(1):70-82
Noninvasive in vivo imaging of pancreatic islet cell biology.
Nat. Med. 2008 May;14(5):574-8