title: Enhanced expression of VEGF-A in β cells increases endothelial cell number but impairs islet morphogenesis and β cell proliferation.
abstract: There is a reciprocal interaction between pancreatic islet cells and vascular endothelial cells (EC) in which EC-derived signals promote islet cell differentiation and islet development while islet cell-derived angiogenic factors promote EC recruitment and extensive islet vascularization. To examine the role of angiogenic factors in the coordinated development of islets and their associated vessels, we used a "tet-on" inducible system (mice expressing rat insulin promoter-reverse tetracycline activator transgene and a tet-operon-angiogenic factor transgene) to increase the β cell production of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (Ang1), or angiopoietin-2 (Ang2) during islet cell differentiation and islet development. In VEGF-A overexpressing embryos, ECs began to accumulate around epithelial tubes residing in the central region of the developing pancreas (associated with endocrine cells) as early as embryonic day 12.5 (E12.5) and increased dramatically by E16.5. While α and β cells formed islet cell clusters in control embryos at E16.5, the increased EC population perturbed endocrine cell differentiation and islet cell clustering in VEGF-A overexpressing embryos. With continued overexpression of VEGF-A, α and β cells became scattered, remained adjacent to ductal structures, and never coalesced into islets, resulting in a reduction in β cell proliferation and β cell mass at postnatal day 1. A similar impact on islet morphology was observed when VEGF-A was overexpressed in β cells during the postnatal period. In contrast, increased expression of Ang1 or Ang2 in β cells in developing or adult islets did not alter islet differentiation, development, or morphology, but altered islet EC ultrastructure. These data indicate that (1) increased EC number does not promote, but actually impairs β cell proliferation and islet formation; (2) the level of VEGF-A production by islet endocrine cells is critical for islet vascularization during development and postnatally; (3) angiopoietin-Tie2 signaling in endothelial cells does not have a crucial role in the development or maintenance of islet vascularization.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cai
authors.forename: Marcela
authors.initials: M
authors.lastname: Brissova
authors.forename: Rachel B
authors.initials: RB
authors.lastname: Reinert
authors.forename: Fong Cheng
authors.initials: FC
authors.lastname: Pan
authors.forename: Priyanka
authors.initials: P
authors.lastname: Brahmachary
authors.forename: Marie
authors.initials: M
authors.lastname: Jeansson
authors.forename: Alena
authors.initials: A
authors.lastname: Shostak
authors.forename: Aramandla
authors.initials: A
authors.lastname: Radhika
authors.forename: Greg
authors.initials: G
authors.lastname: Poffenberger
authors.forename: Susan E
authors.initials: SE
authors.lastname: Quaggin
authors.forename: W Gray
authors.initials: WG
authors.lastname: Jerome
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dumont
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D002452:Cell Count; D042783:Endothelial Cells / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000098:blood supply / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse