Journal
DEVELOPMENT
Volume 141, Issue 7, Pages 1480-1491Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.098657
Keywords
VEGF; Endothelial cell; Innervation; Islet; Vascularization
Categories
Funding
- Department of Veterans Affairs [BX000666]
- Juvenile Diabetes Research Foundation (JDRF)
- National Institutes of Health (NIH) [DK66636, DK69603, DK63439, DK62641, DK72473, DK89572, DK89538, HD36720, R56 DK71052, F30 DK85932, T32 GM07347]
- Vanderbilt Diabetes Research and Training Center [DK20593]
- Vanderbilt Diabetes Research and Training Center
- NIH [DK20593, CA68485, DK58404, HD15052, DK59637, EY08126]
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Neurovascular alignment is a common anatomical feature of organs, but the mechanisms leading to this arrangement are incompletely understood. Here, we show that vascular endothelial growth factor (VEGF) signaling profoundly affects both vascularization and innervation of the pancreatic islet. In mature islets, nerves are closely associated with capillaries, but the islet vascularization process during embryonic organogenesis significantly precedes islet innervation. Although a simple neuronal meshwork interconnects the developing islet clusters as they begin to form at E14.5, the substantial ingrowth of nerve fibers into islets occurs postnatally, when islet vascularization is already complete. Using genetic mouse models, we demonstrate that VEGF regulates islet innervation indirectly through its effects on intra-islet endothelial cells. Our data indicate that formation of a VEGF directed, intra-islet vascular plexus is required for development of islet innervation, and that VEGFinduced islet hypervascularization leads to increased nerve fiber ingrowth. Transcriptome analysis of hypervascularized islets revealed an increased expression of extracellular matrix components and axon guidance molecules, with these transcripts being enriched in the isletderived endothelial cell population. We propose a mechanism for coordinated neurovascular development within pancreatic islets, in which endocrine cell-derived VEGF directs the patterning of intra-islet capillaries during embryogenesis, forming a scaffold for the postnatal ingrowth of essential autonomic nerve fibers.
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