title: Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding.
abstract: 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 VEGF-induced 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 islet-derived 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Reinert
authors.forename: Qing
authors.initials: Q
authors.lastname: Cai
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Plank
authors.forename: Kristie
authors.initials: K
authors.lastname: Aamodt
authors.forename: Nripesh
authors.initials: N
authors.lastname: Prasad
authors.forename: Radhika
authors.initials: R
authors.lastname: Aramandla
authors.forename: Chunhua
authors.initials: C
authors.lastname: Dai
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Levy
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Labosky
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.forename: Marcela
authors.initials: M
authors.lastname: Brissova
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000196:embryology / Q000502:physiology*; D002450:Cell Communication / Q000235:genetics*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004730:Endothelium, Vascular / Q000196:embryology / Q000378:metabolism / Q000502:physiology; D005260:Female; D007515:Islets of Langerhans / Q000098:blood supply* / Q000196:embryology / Q000294:innervation*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: Endothelial cell; Innervation; Islet; VEGF; Vascularization