Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding
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 mat...
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Veröffentlicht in: | Development (Cambridge) 2014-04, Vol.141 (7), p.1480-1491 |
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creator | Reinert, Rachel B Cai, Qing Hong, Ji-Young Plank, Jennifer L Aamodt, Kristie Prasad, Nripesh Aramandla, Radhika Dai, Chunhua Levy, Shawn E Pozzi, Ambra Labosky, Patricia A Wright, Christopher V E Brissova, Marcela Powers, Alvin C |
description | 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. |
doi_str_mv | 10.1242/dev.098657 |
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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.</description><identifier>ISSN: 0950-1991</identifier><identifier>EISSN: 1477-9129</identifier><identifier>DOI: 10.1242/dev.098657</identifier><identifier>PMID: 24574008</identifier><language>eng</language><publisher>England: Company of Biologists</publisher><subject>Animals ; Blood Vessels - embryology ; Blood Vessels - physiology ; Cell Communication - genetics ; Cells, Cultured ; Embryo, Mammalian ; Endothelium, Vascular - embryology ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - physiology ; Female ; Islets of Langerhans - blood supply ; Islets of Langerhans - embryology ; Islets of Langerhans - innervation ; Mice ; Mice, Transgenic ; Neovascularization, Physiologic - physiology ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - physiology</subject><ispartof>Development (Cambridge), 2014-04, Vol.141 (7), p.1480-1491</ispartof><rights>2014. 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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.</description><subject>Animals</subject><subject>Blood Vessels - embryology</subject><subject>Blood Vessels - physiology</subject><subject>Cell Communication - genetics</subject><subject>Cells, Cultured</subject><subject>Embryo, Mammalian</subject><subject>Endothelium, Vascular - embryology</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Endothelium, Vascular - physiology</subject><subject>Female</subject><subject>Islets of Langerhans - blood supply</subject><subject>Islets of Langerhans - embryology</subject><subject>Islets of Langerhans - innervation</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Neovascularization, Physiologic - physiology</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor A - physiology</subject><issn>0950-1991</issn><issn>1477-9129</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU1rGzEQhkVpqJ20l_yAsMcSWEerD2t1CYSQpAVDLm2hJzGrHdkK8sqR5A3599ngJLQwMId5eGaYl5DThi4aJthFj-OC6nYp1Scyb4RStW6Y_kzmVEtaN1o3M3Kc8wOllC-V-kJmTEglKG3n5O8fyHYfIFU49LFsMHgI1TrFp7KpHNgSU2VjTL0foGCufA5YKj8MmEYoPg7V6KEa3yXZgnMxTPT6KzlyEDJ-e-sn5Pftza_rH_Xq_u7n9dWqtkKIUqNwnZWIkrVCWtkxWLadbZeOUUABrHXoOOsEKEBN0fIOOHKQVjM5Vc9PyOXBu9t3W-wtDiVBMLvkt5CeTQRv_p8MfmPWcTRcS8UVmwTf3wQpPu4xF7P12WIIMGDcZ9NI2mrBKX1Fzw-oTTHnhO5jTUPNaxZmysIcspjgs38P-0Dfn89fAOMJiP4</recordid><startdate>201404</startdate><enddate>201404</enddate><creator>Reinert, Rachel B</creator><creator>Cai, Qing</creator><creator>Hong, Ji-Young</creator><creator>Plank, Jennifer L</creator><creator>Aamodt, Kristie</creator><creator>Prasad, Nripesh</creator><creator>Aramandla, Radhika</creator><creator>Dai, Chunhua</creator><creator>Levy, Shawn E</creator><creator>Pozzi, Ambra</creator><creator>Labosky, Patricia A</creator><creator>Wright, Christopher V E</creator><creator>Brissova, Marcela</creator><creator>Powers, Alvin C</creator><general>Company of Biologists</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201404</creationdate><title>Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding</title><author>Reinert, Rachel B ; Cai, Qing ; Hong, Ji-Young ; Plank, Jennifer L ; Aamodt, Kristie ; Prasad, Nripesh ; Aramandla, Radhika ; Dai, Chunhua ; Levy, Shawn E ; Pozzi, Ambra ; Labosky, Patricia A ; Wright, Christopher V E ; Brissova, Marcela ; Powers, Alvin C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c444t-e4fbc5ee52845c5b2a68bc86f20ae4a28fef32b4a7ae90ec3ba3e3a5c925925d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Blood Vessels - embryology</topic><topic>Blood Vessels - physiology</topic><topic>Cell Communication - genetics</topic><topic>Cells, Cultured</topic><topic>Embryo, Mammalian</topic><topic>Endothelium, Vascular - embryology</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Endothelium, Vascular - physiology</topic><topic>Female</topic><topic>Islets of Langerhans - blood supply</topic><topic>Islets of Langerhans - embryology</topic><topic>Islets of Langerhans - innervation</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Neovascularization, Physiologic - physiology</topic><topic>Vascular Endothelial Growth Factor A - genetics</topic><topic>Vascular Endothelial Growth Factor A - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Reinert, Rachel B</creatorcontrib><creatorcontrib>Cai, Qing</creatorcontrib><creatorcontrib>Hong, Ji-Young</creatorcontrib><creatorcontrib>Plank, Jennifer L</creatorcontrib><creatorcontrib>Aamodt, Kristie</creatorcontrib><creatorcontrib>Prasad, Nripesh</creatorcontrib><creatorcontrib>Aramandla, Radhika</creatorcontrib><creatorcontrib>Dai, Chunhua</creatorcontrib><creatorcontrib>Levy, Shawn E</creatorcontrib><creatorcontrib>Pozzi, Ambra</creatorcontrib><creatorcontrib>Labosky, Patricia A</creatorcontrib><creatorcontrib>Wright, Christopher V E</creatorcontrib><creatorcontrib>Brissova, Marcela</creatorcontrib><creatorcontrib>Powers, Alvin C</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Development (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Reinert, Rachel B</au><au>Cai, Qing</au><au>Hong, Ji-Young</au><au>Plank, Jennifer L</au><au>Aamodt, Kristie</au><au>Prasad, Nripesh</au><au>Aramandla, Radhika</au><au>Dai, Chunhua</au><au>Levy, Shawn E</au><au>Pozzi, Ambra</au><au>Labosky, Patricia A</au><au>Wright, Christopher V E</au><au>Brissova, Marcela</au><au>Powers, Alvin C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding</atitle><jtitle>Development (Cambridge)</jtitle><addtitle>Development</addtitle><date>2014-04</date><risdate>2014</risdate><volume>141</volume><issue>7</issue><spage>1480</spage><epage>1491</epage><pages>1480-1491</pages><issn>0950-1991</issn><eissn>1477-9129</eissn><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.</abstract><cop>England</cop><pub>Company of Biologists</pub><pmid>24574008</pmid><doi>10.1242/dev.098657</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Blood Vessels - embryology Blood Vessels - physiology Cell Communication - genetics Cells, Cultured Embryo, Mammalian Endothelium, Vascular - embryology Endothelium, Vascular - metabolism Endothelium, Vascular - physiology Female Islets of Langerhans - blood supply Islets of Langerhans - embryology Islets of Langerhans - innervation Mice Mice, Transgenic Neovascularization, Physiologic - physiology Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - physiology |
title | Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding |
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