VEGF-B in islet of langerhans : role in vascular signaling and lipid handling

Sammanfattning: The discovery of Vascular endothelial growth factor (VEGF)-B’s role in endothelial fatty acid uptake and tissue lipid accumulation opened a new arena for exploration of VEGF-B in lipid metabolism. Indeed, later studies demonstrated the beneficial/therapeutic effects of reducing VEGF-B signaling systemically. However, the tissue specific role of VEGF-B signaling has yet to be determined and furthermore the contribution of tissue specific VEGF-B activity to the systemic effects is also unknown to date. In paper I, we investigated the role of local VEGF-B signaling in pancreatic islets by employing a novel mouse model where Vegfb in pancreatic β-cells were selectively deleted using Cre/loxP technology. We showed that Vegfb is abundantly expressed in both endocrine and exocrine pancreas, but that ablation of Vegfb from β-cells does not affect systemic glucose homeostasis or islet lipid uptake under chow or high-fat diet (HFD) conditions. However, deletion of Vegfb in pancreatic β-cells increased insulin (Ins2) gene expression, which indicates the potential interaction between VEGF-B signaling and transcriptional regulation of insulin, a phenotype warranting further studies. In paper II, we continued to explore the role of pancreatic β-cell derived VEGF-B in systemic homeostasis. In contrast to the mouse model used in paper I, we utilized a mouse model where the human VEGF-B167 isoform is overexpressed in pancreatic β-cells (under the rat insulin promoter). In this study, we could demonstrate that overexpression of VEGF-B in pancreatic β-cells does not affect systemic glucose homeostasis under chow or HFD conditions. Unexpectedly, overexpression of VEGF-B in pancreatic islets led to increased plasma triglycerides. This could indicate VEGF-B’s involvement in plasma lipoprotein synthesis or degradation, and further studies are needed to elucidate this effect. The role of VEGF-B in angiogenesis is somewhat ambiguous. To address this question, in paper III, we deployed a newly developed intravital imaging protocol where isolated mouse islets were transplanted into the anterior chamber of the eye to facilitate the observation of islet vessel development, pharmacological treatment of tumor islets and effects of VEGF-B overexpression in β-cells. We showed that the advantage of this platform comprises high spatial resolution, real-time monitoring of islet development and feasibility for evaluating efficacy of pharmacological treatments of tumor islets. In addition, we observed that overexpression of VEGF-B in tumor islets increased tumor angiogenesis but impaired tumor growth, providing additional information about the role of VEGF-B in pathological angiogenesis. Canonical Wnt/β-catenin signaling is essential for the retinal and cerebral angiogenesis during development. However, little is known regarding the contribution of endothelial β-catenin signaling in postnatal central nervous system (CNS) and potential interaction with other signaling pathways regulating angiogenesis. In paper IV, we studied the role of endothelial β-catenin signaling in central nervous system angiogenesis. We demonstrated that impaired Wnt/β-catenin signaling resulted in reduced postnatal retinal- and cerebral angiogenesis, presumably by diminished VEGFR2 expression. We furthermore identified crosstalk between the Wnt/β-catenin and Notch/VEGFA signaling pathways. In summary, this thesis provides further knowledge about the specific role of VEGF-B signaling in islets of Langerhans, and its effects on systemic glucose homeostasis and lipid handling. Additionally, development of a novel intravital imaging protocol, as well as uncovering of additional roles of endothelial Wnt/β-catenin signaling in CNS, constitute parts of this thesis.