Blood vessels restrain pancreas branching, differentiation and growth

How organ size and form are controlled during development is a major question of biology. Blood vessels have been shown to be essential for early development of the liver and pancreas, and are fundamental to normal and pathological tissue growth. Here we report that non-nutritional signals from blood vessels surprisingly act to restrain pancreas growth. Elimination of endothelial cells increases the size of embryonic pancreatic buds. Conversely, VEGF-induced hypervascularization decreases pancreas size. The growth phenotype results from vascular restriction of pancreatic tip cell formation, lateral branching and differentiation of the pancreatic epithelium into endocrine and acinar cells. The effects are seen both in vivo and ex vivo, indicating a perfusion-independent mechanism. Thus the vasculature controls pancreas morphogenesis and growth by reducing branching and differentiation of primitive epithelial cells. For transcriptome analysis, RNA was isolated using QIAGEN RNeasy micro Kit from pancreatic buds of Pdx1-tTA (n=3) and littermate Pdx1-tTA; TET-VEGF (n=3) e12.5 embryos, or from e12.5 wild type pancreatic buds explanted and treated with VEGFR2i (n=5) or vehicle (n=5) for 2 days. Pooled samples were hybridized to Affymetrix mouse gene 1.0 st arrays. The arrays were RMA normalized using Partek Genomic Suite 6.5. Differentially regulated genes were selected based on p-values and ratios using t-test.