Abstract
An important question is how growing tissues establish a blood vessel network. Here we study vascular network formation in pancreatic islets, endocrine tissues derived from pancreatic epithelium. We find that depletion of integrin-linked kinase (ILK) in the pancreatic epithelial cells of mice results in glucose intolerance due to a loss of the intra-islet vasculature. In turn, blood vessels accumulate at the islet periphery. Neither alterations in endothelial cell proliferation, apoptosis, morphology, Vegfa expression and VEGF-A secretion nor ‘empty sleeves' of vascular basement membrane are found. Instead, biophysical experiments reveal that the biomechanical properties of pancreatic islet cells, such as their actomyosin-mediated cortex tension and adhesive forces to endothelial cells, are significantly changed. These results suggest that a sorting event is driving the segregation of endothelial and epithelial cells and indicate that the epithelial biomechanical properties determine whether the blood vasculature invades or envelops a growing epithelial tissue.
Highlights
An important question is how growing tissues establish a blood vessel network
To further describe the glucose intolerance and delayed insulin release observed in integrin-linked kinase (ILK) cKO mice, we investigated whether the islet capillaries were perfused
A strong reduction of Ilk messenger RNA and protein expression was observed in ILK cKO islets compared with those of heterozygous control islets (Supplementary Fig. 1a,b)
Summary
An important question is how growing tissues establish a blood vessel network. Here we study vascular network formation in pancreatic islets, endocrine tissues derived from pancreatic epithelium. We investigated the role of ILK in islet endocrine cells in vitro and in vivo and found that knockdown of Ilk in mouse insulinoma cells and deletion of Ilk in the pancreatic epithelium of mice reduce the adhesion strength of the endocrine cells to a vascular endothelial cell line, while at the same time increase cortex tension of the endocrine cells. The latter findings help to explain why deletion of Ilk in pancreatic epithelium leads to a loss of the intra-islet vasculature and excessive accumulation of the vasculature at the islet periphery. After injection of a fluorescein isothiocyanate (FITC)-labelled tomato lectin into the tail vein of mice, all analysed islet vessels were coated with the fluorescent lectin (Supplementary Fig. 4b), indicating that the blood vessels in ILK cKO islets were perfused despite their altered localization
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