The purpose 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 the mechanisms that regulates vascular growth, both physiological (angiogenesis) and pathophysiological (e.g. tumor angiogenesis), and organ specific specialization of vascular beds.
Endothelial Wnt/beta-catenin signaling in vascular development
The Wnt pathway 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 the phosphorylation and degradation of beta-catenin, and enables beta-catenin to accumulate and translocate to the nucleus to activate gene transcription. In addition to its role as a transcription factor, beta-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/beta-catenin signaling in retinal vascular development. Notably, Wnt/beta-catenin signaling is vital for differentiation of the blood-brain barrier (BBB).
Our research is focused on elucidating the role of endothelial Wnt/beta-catenin signaling in vascular development. We have previously found that endothelial Wnt/beta-catenin is an important player during embryonic vascular development by modulating vessel remodeling and up-regulating Dll4/Notch signaling (Corada, Nyqvist et al., Dev Cell 2010). We are now investigating the role of endothelial Wnt/beta-catenin signaling during post-natal vascular developmental and tumor angiogenesis.
VEGF-B signaling in pancreatic beta-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 (Hagberg et al., Nature 2010). Now we 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 (Hagberg, Mehlem et al., Nature 2012). These findings underscore an important role for the endothelium as a barrier for lipid transport, and for VEGF-B as a therapeutic candidate in type 2 diabetes.
The goal of this project is to elucidate the role of paracrine VEGF-B signaling for lipid uptake to pancreatic islets and insulin producing beta-cells. Extensive research has identified increased and dysregulated lipid handling as a early hallmark of beta-cell dysfunction and failure during development of type 2 diabetes.