VEGF-Dependent Conjunctivalization of the Corneal Surface
To investigate the mechanisms governing corneal neovascularization and the appearance of goblet cells in a murine model of limbal insufficiency. The spatial and time-dependent relationship between corneal neovascularization and goblet cell density was analyzed in corneal flatmounts. Immunohistochemi...
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| Veröffentlicht in: | Investigative ophthalmology & visual science 2003-01, Vol.44 (1), p.117-123 |
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| creator | Joussen, Antonia M Poulaki, Vassiliki Mitsiades, Nicholas Stechschulte, Stephen U Kirchhof, Bernd Dartt, Darlene A Fong, Guo-Hua Rudge, John Wiegand, Stanley J Yancopoulos, George D Adamis, Anthony P |
| description | To investigate the mechanisms governing corneal neovascularization and the appearance of goblet cells in a murine model of limbal insufficiency.
The spatial and time-dependent relationship between corneal neovascularization and goblet cell density was analyzed in corneal flatmounts. Immunohistochemical detection of the vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR1) was performed in paraffin-embedded sections. A transgenic mouse that expresses the reporter gene lacZ targeted to the Flt-1 locus through homologous recombination was used to analyze corneal expression of Flt-1. The presence of soluble and membranous goblet cell Flt-1 mRNA and protein content was assessed with Northern and Western blot analyses, respectively. Finally, systemic adenoviral expression of a soluble Flt-1/Fc construct was used to study the effect of inhibition of VEGF bioactivity on the appearance of goblet cells and neovascularization.
Corneal neovascularization preceded the appearance of goblet cells, although both processes overlapped temporally. Flt-1 was abundant in the conjunctiva-like epithelium covering the cornea, as well as in the goblet cells, invading leukocytes, and vasculature. A similar expression pattern was observed in the transgenic mice expressing the lacZ gene downstream from the Flt-1 promoter. Isolated human and rat goblet cells in culture expressed Flt-1 mRNA and protein, as did freshly isolated human conjunctiva. The systemic inhibition of VEGF bioactivity potently suppressed both corneal neovascularization (8.3% +/- 8.1% vs. 41.1% +/- 15.3% corneal area; P < 0.001) and corneal goblet cell density (1.6% +/- 2.5% vs. 12.2% +/- 2.4% corneal area; P < 0.001).
Two important features of corneal conjunctivalization, the appearance of goblet cells and neovascularization, are regulated by VEGF. Both processes are probably mediated, in part, through the Flt-1 receptor. Taken together, these data indicate that an anti-VEGF therapeutic approach may limit the visual loss associated with conjunctivalization of the corneal surface. |
| doi_str_mv | 10.1167/iovs.01-1277 |
| format | Article |
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The spatial and time-dependent relationship between corneal neovascularization and goblet cell density was analyzed in corneal flatmounts. Immunohistochemical detection of the vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR1) was performed in paraffin-embedded sections. A transgenic mouse that expresses the reporter gene lacZ targeted to the Flt-1 locus through homologous recombination was used to analyze corneal expression of Flt-1. The presence of soluble and membranous goblet cell Flt-1 mRNA and protein content was assessed with Northern and Western blot analyses, respectively. Finally, systemic adenoviral expression of a soluble Flt-1/Fc construct was used to study the effect of inhibition of VEGF bioactivity on the appearance of goblet cells and neovascularization.
Corneal neovascularization preceded the appearance of goblet cells, although both processes overlapped temporally. Flt-1 was abundant in the conjunctiva-like epithelium covering the cornea, as well as in the goblet cells, invading leukocytes, and vasculature. A similar expression pattern was observed in the transgenic mice expressing the lacZ gene downstream from the Flt-1 promoter. Isolated human and rat goblet cells in culture expressed Flt-1 mRNA and protein, as did freshly isolated human conjunctiva. The systemic inhibition of VEGF bioactivity potently suppressed both corneal neovascularization (8.3% +/- 8.1% vs. 41.1% +/- 15.3% corneal area; P < 0.001) and corneal goblet cell density (1.6% +/- 2.5% vs. 12.2% +/- 2.4% corneal area; P < 0.001).
Two important features of corneal conjunctivalization, the appearance of goblet cells and neovascularization, are regulated by VEGF. Both processes are probably mediated, in part, through the Flt-1 receptor. Taken together, these data indicate that an anti-VEGF therapeutic approach may limit the visual loss associated with conjunctivalization of the corneal surface.</description><identifier>ISSN: 0146-0404</identifier><identifier>ISSN: 1552-5783</identifier><identifier>EISSN: 1552-5783</identifier><identifier>DOI: 10.1167/iovs.01-1277</identifier><identifier>PMID: 12506063</identifier><identifier>CODEN: IOVSDA</identifier><language>eng</language><publisher>Rockville, MD: ARVO</publisher><subject>Animals ; beta-Galactosidase - metabolism ; Biological and medical sciences ; Blotting, Northern ; Blotting, Western ; Cell Count ; Conjunctiva - metabolism ; Conjunctiva - pathology ; Corneal Neovascularization - metabolism ; Corneal Neovascularization - pathology ; Diseases of cornea, anterior segment and sclera ; Endothelial Growth Factors - metabolism ; Epithelial Cells - pathology ; Goblet Cells - pathology ; Immunoenzyme Techniques ; Intercellular Signaling Peptides and Proteins - metabolism ; Lymphokines - metabolism ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Ophthalmology ; RNA, Messenger - metabolism ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor Receptor-1 - genetics ; Vascular Endothelial Growth Factor Receptor-1 - metabolism ; Vascular Endothelial Growth Factors</subject><ispartof>Investigative ophthalmology & visual science, 2003-01, Vol.44 (1), p.117-123</ispartof><rights>2003 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c385t-ec8f8da2cc09670b13047529817b3fc73fe4aeeba1497b9d1becfc181ac75983</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,4009,27902,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14454417$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12506063$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Joussen, Antonia M</creatorcontrib><creatorcontrib>Poulaki, Vassiliki</creatorcontrib><creatorcontrib>Mitsiades, Nicholas</creatorcontrib><creatorcontrib>Stechschulte, Stephen U</creatorcontrib><creatorcontrib>Kirchhof, Bernd</creatorcontrib><creatorcontrib>Dartt, Darlene A</creatorcontrib><creatorcontrib>Fong, Guo-Hua</creatorcontrib><creatorcontrib>Rudge, John</creatorcontrib><creatorcontrib>Wiegand, Stanley J</creatorcontrib><creatorcontrib>Yancopoulos, George D</creatorcontrib><creatorcontrib>Adamis, Anthony P</creatorcontrib><title>VEGF-Dependent Conjunctivalization of the Corneal Surface</title><title>Investigative ophthalmology & visual science</title><addtitle>Invest Ophthalmol Vis Sci</addtitle><description>To investigate the mechanisms governing corneal neovascularization and the appearance of goblet cells in a murine model of limbal insufficiency.
The spatial and time-dependent relationship between corneal neovascularization and goblet cell density was analyzed in corneal flatmounts. Immunohistochemical detection of the vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR1) was performed in paraffin-embedded sections. A transgenic mouse that expresses the reporter gene lacZ targeted to the Flt-1 locus through homologous recombination was used to analyze corneal expression of Flt-1. The presence of soluble and membranous goblet cell Flt-1 mRNA and protein content was assessed with Northern and Western blot analyses, respectively. Finally, systemic adenoviral expression of a soluble Flt-1/Fc construct was used to study the effect of inhibition of VEGF bioactivity on the appearance of goblet cells and neovascularization.
Corneal neovascularization preceded the appearance of goblet cells, although both processes overlapped temporally. Flt-1 was abundant in the conjunctiva-like epithelium covering the cornea, as well as in the goblet cells, invading leukocytes, and vasculature. A similar expression pattern was observed in the transgenic mice expressing the lacZ gene downstream from the Flt-1 promoter. Isolated human and rat goblet cells in culture expressed Flt-1 mRNA and protein, as did freshly isolated human conjunctiva. The systemic inhibition of VEGF bioactivity potently suppressed both corneal neovascularization (8.3% +/- 8.1% vs. 41.1% +/- 15.3% corneal area; P < 0.001) and corneal goblet cell density (1.6% +/- 2.5% vs. 12.2% +/- 2.4% corneal area; P < 0.001).
Two important features of corneal conjunctivalization, the appearance of goblet cells and neovascularization, are regulated by VEGF. Both processes are probably mediated, in part, through the Flt-1 receptor. Taken together, these data indicate that an anti-VEGF therapeutic approach may limit the visual loss associated with conjunctivalization of the corneal surface.</description><subject>Animals</subject><subject>beta-Galactosidase - metabolism</subject><subject>Biological and medical sciences</subject><subject>Blotting, Northern</subject><subject>Blotting, Western</subject><subject>Cell Count</subject><subject>Conjunctiva - metabolism</subject><subject>Conjunctiva - pathology</subject><subject>Corneal Neovascularization - metabolism</subject><subject>Corneal Neovascularization - pathology</subject><subject>Diseases of cornea, anterior segment and sclera</subject><subject>Endothelial Growth Factors - metabolism</subject><subject>Epithelial Cells - pathology</subject><subject>Goblet Cells - pathology</subject><subject>Immunoenzyme Techniques</subject><subject>Intercellular Signaling Peptides and Proteins - metabolism</subject><subject>Lymphokines - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Ophthalmology</subject><subject>RNA, Messenger - metabolism</subject><subject>Vascular Endothelial Growth Factor A</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - genetics</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - metabolism</subject><subject>Vascular Endothelial Growth Factors</subject><issn>0146-0404</issn><issn>1552-5783</issn><issn>1552-5783</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpF0M9LwzAYxvEgipvTm2fZRU925k3Tpj3K3KYw8ODwGtL0jcvoj5m0K_rX22Fhpxzy4XnhS8gt0BlALJ5sffAzCgEwIc7IGKKIBZFIwnMypsDjgHLKR-TK-x2lDIDRSzICFtGYxuGYpJ-L1TJ4wT1WOVbNdF5Xu7bSjT2owv6qxtbVtDbTZov9l6tQFdOP1hml8ZpcGFV4vBneCdksF5v5a7B-X73Nn9eBDpOoCVAnJskV05qmsaAZhJSLiKUJiCw0WoQGuULMFPBUZGkOGWqjIQGlRZQm4YQ8_M_uXf3dom9kab3GolAV1q2XgqWcxRD38PEfald779DIvbOlcj8SqDyWksdSkoI8lur53bDbZiXmJzyk6cH9AJTXqjBOVdr6k-M84hzEyW3t17azDqUvVVH0syC7ruNc9hd79we-Dn3-</recordid><startdate>20030101</startdate><enddate>20030101</enddate><creator>Joussen, Antonia M</creator><creator>Poulaki, Vassiliki</creator><creator>Mitsiades, Nicholas</creator><creator>Stechschulte, Stephen U</creator><creator>Kirchhof, Bernd</creator><creator>Dartt, Darlene A</creator><creator>Fong, Guo-Hua</creator><creator>Rudge, John</creator><creator>Wiegand, Stanley J</creator><creator>Yancopoulos, George D</creator><creator>Adamis, Anthony P</creator><general>ARVO</general><general>Association for Research in Vision and Ophtalmology</general><scope>IQODW</scope><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></search><sort><creationdate>20030101</creationdate><title>VEGF-Dependent Conjunctivalization of the Corneal Surface</title><author>Joussen, Antonia M ; Poulaki, Vassiliki ; Mitsiades, Nicholas ; Stechschulte, Stephen U ; Kirchhof, Bernd ; Dartt, Darlene A ; Fong, Guo-Hua ; Rudge, John ; Wiegand, Stanley J ; Yancopoulos, George D ; Adamis, Anthony P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c385t-ec8f8da2cc09670b13047529817b3fc73fe4aeeba1497b9d1becfc181ac75983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>beta-Galactosidase - metabolism</topic><topic>Biological and medical sciences</topic><topic>Blotting, Northern</topic><topic>Blotting, Western</topic><topic>Cell Count</topic><topic>Conjunctiva - metabolism</topic><topic>Conjunctiva - pathology</topic><topic>Corneal Neovascularization - metabolism</topic><topic>Corneal Neovascularization - pathology</topic><topic>Diseases of cornea, anterior segment and sclera</topic><topic>Endothelial Growth Factors - metabolism</topic><topic>Epithelial Cells - pathology</topic><topic>Goblet Cells - pathology</topic><topic>Immunoenzyme Techniques</topic><topic>Intercellular Signaling Peptides and Proteins - metabolism</topic><topic>Lymphokines - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Ophthalmology</topic><topic>RNA, Messenger - metabolism</topic><topic>Vascular Endothelial Growth Factor A</topic><topic>Vascular Endothelial Growth Factor Receptor-1 - genetics</topic><topic>Vascular Endothelial Growth Factor Receptor-1 - metabolism</topic><topic>Vascular Endothelial Growth Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Joussen, Antonia M</creatorcontrib><creatorcontrib>Poulaki, Vassiliki</creatorcontrib><creatorcontrib>Mitsiades, Nicholas</creatorcontrib><creatorcontrib>Stechschulte, Stephen U</creatorcontrib><creatorcontrib>Kirchhof, Bernd</creatorcontrib><creatorcontrib>Dartt, Darlene A</creatorcontrib><creatorcontrib>Fong, Guo-Hua</creatorcontrib><creatorcontrib>Rudge, John</creatorcontrib><creatorcontrib>Wiegand, Stanley J</creatorcontrib><creatorcontrib>Yancopoulos, George D</creatorcontrib><creatorcontrib>Adamis, Anthony P</creatorcontrib><collection>Pascal-Francis</collection><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><jtitle>Investigative ophthalmology & visual science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Joussen, Antonia M</au><au>Poulaki, Vassiliki</au><au>Mitsiades, Nicholas</au><au>Stechschulte, Stephen U</au><au>Kirchhof, Bernd</au><au>Dartt, Darlene A</au><au>Fong, Guo-Hua</au><au>Rudge, John</au><au>Wiegand, Stanley J</au><au>Yancopoulos, George D</au><au>Adamis, Anthony P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>VEGF-Dependent Conjunctivalization of the Corneal Surface</atitle><jtitle>Investigative ophthalmology & visual science</jtitle><addtitle>Invest Ophthalmol Vis Sci</addtitle><date>2003-01-01</date><risdate>2003</risdate><volume>44</volume><issue>1</issue><spage>117</spage><epage>123</epage><pages>117-123</pages><issn>0146-0404</issn><issn>1552-5783</issn><eissn>1552-5783</eissn><coden>IOVSDA</coden><abstract>To investigate the mechanisms governing corneal neovascularization and the appearance of goblet cells in a murine model of limbal insufficiency.
The spatial and time-dependent relationship between corneal neovascularization and goblet cell density was analyzed in corneal flatmounts. Immunohistochemical detection of the vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR1) was performed in paraffin-embedded sections. A transgenic mouse that expresses the reporter gene lacZ targeted to the Flt-1 locus through homologous recombination was used to analyze corneal expression of Flt-1. The presence of soluble and membranous goblet cell Flt-1 mRNA and protein content was assessed with Northern and Western blot analyses, respectively. Finally, systemic adenoviral expression of a soluble Flt-1/Fc construct was used to study the effect of inhibition of VEGF bioactivity on the appearance of goblet cells and neovascularization.
Corneal neovascularization preceded the appearance of goblet cells, although both processes overlapped temporally. Flt-1 was abundant in the conjunctiva-like epithelium covering the cornea, as well as in the goblet cells, invading leukocytes, and vasculature. A similar expression pattern was observed in the transgenic mice expressing the lacZ gene downstream from the Flt-1 promoter. Isolated human and rat goblet cells in culture expressed Flt-1 mRNA and protein, as did freshly isolated human conjunctiva. The systemic inhibition of VEGF bioactivity potently suppressed both corneal neovascularization (8.3% +/- 8.1% vs. 41.1% +/- 15.3% corneal area; P < 0.001) and corneal goblet cell density (1.6% +/- 2.5% vs. 12.2% +/- 2.4% corneal area; P < 0.001).
Two important features of corneal conjunctivalization, the appearance of goblet cells and neovascularization, are regulated by VEGF. Both processes are probably mediated, in part, through the Flt-1 receptor. Taken together, these data indicate that an anti-VEGF therapeutic approach may limit the visual loss associated with conjunctivalization of the corneal surface.</abstract><cop>Rockville, MD</cop><pub>ARVO</pub><pmid>12506063</pmid><doi>10.1167/iovs.01-1277</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals beta-Galactosidase - metabolism Biological and medical sciences Blotting, Northern Blotting, Western Cell Count Conjunctiva - metabolism Conjunctiva - pathology Corneal Neovascularization - metabolism Corneal Neovascularization - pathology Diseases of cornea, anterior segment and sclera Endothelial Growth Factors - metabolism Epithelial Cells - pathology Goblet Cells - pathology Immunoenzyme Techniques Intercellular Signaling Peptides and Proteins - metabolism Lymphokines - metabolism Male Medical sciences Mice Mice, Inbred C57BL Mice, Transgenic Ophthalmology RNA, Messenger - metabolism Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor-1 - genetics Vascular Endothelial Growth Factor Receptor-1 - metabolism Vascular Endothelial Growth Factors |
| title | VEGF-Dependent Conjunctivalization of the Corneal Surface |
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