AIP1 mediates VEGFR-3-dependent angiogenic and lymphangiogenic responses
Identifieur interne : 006153 ( Ncbi/Merge ); précédent : 006152; suivant : 006154AIP1 mediates VEGFR-3-dependent angiogenic and lymphangiogenic responses
Auteurs : Huanjiao Jenny Zhou [États-Unis, République populaire de Chine] ; Xiaodong Chen [États-Unis, République populaire de Chine] ; Renjing Liu [Australie] ; Haifeng Zhang [États-Unis] ; Yingdi Wang [États-Unis] ; Yu Jin [États-Unis] ; Xiaoling Liang [République populaire de Chine] ; Lin Lu [République populaire de Chine] ; Zhe Xu ; Wang Min [États-Unis]Source :
- Arteriosclerosis, thrombosis, and vascular biology [ 1079-5642 ] ; 2014.
Abstract
To investigate the novel function of AIP1 in VEGFR-3 signaling, and VEGFR-3-dependent angiogenesis and lymphangiogenesis.
AIP1, a signaling scaffold protein, is highly expressed in the vascular endothelium. We have previously reported that AIP1 functions as an endogenous inhibitor in pathological angiogenesis by blocking VEGFR-2 activity. Surprisingly, here we observe that mice with a global deletion of AIP1 (AIP1-KO) exhibit reduced retinal angiogenesis with less sprouting and fewer branches. Vascular endothelial cell (but not neuronal)-specific deletion of AIP1 causes similar defects in retinal angiogenesis. The reduced retinal angiogenesis correlates with reduced expression in VEGFR-3 despite increased VEGFR-2 levels in AIP1-KO retinas. Consistent with the reduced expression of VEGFR-3, AIP1-KO mice show delayed developmental lymphangiogenesis in neonatal skin and mesentery, and mount weaker VEGF-C-induced cornea lymphangiogenesis. In vitro, human lymphatic EC with AIP1 siRNA knockdown, retinal EC and lymphatic EC isolated from AIP1-KO all show attenuated VEGF-C-induced VEGFR-3 signaling. Mechanistically, we demonstrate that AIP1 via
Our in vivo and in vitro results provide the first insight into the mechanism by which AIP1 mediates VEGFR-3-dependent angiogenic and lymphangiogenic signaling.
Url:
DOI: 10.1161/ATVBAHA.113.303053
PubMed: 24407031
PubMed Central: 3952062
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<author><name sortKey="Min, Wang" sort="Min, Wang" uniqKey="Min W" first="Wang" last="Min">Wang Min</name>
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<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Objective</title>
<p id="P1">To investigate the novel function of AIP1 in VEGFR-3 signaling, and VEGFR-3-dependent angiogenesis and lymphangiogenesis.</p>
</sec>
<sec id="S2"><title>Approach/Results</title>
<p id="P2">AIP1, a signaling scaffold protein, is highly expressed in the vascular endothelium. We have previously reported that AIP1 functions as an endogenous inhibitor in pathological angiogenesis by blocking VEGFR-2 activity. Surprisingly, here we observe that mice with a global deletion of AIP1 (AIP1-KO) exhibit reduced retinal angiogenesis with less sprouting and fewer branches. Vascular endothelial cell (but not neuronal)-specific deletion of AIP1 causes similar defects in retinal angiogenesis. The reduced retinal angiogenesis correlates with reduced expression in VEGFR-3 despite increased VEGFR-2 levels in AIP1-KO retinas. Consistent with the reduced expression of VEGFR-3, AIP1-KO mice show delayed developmental lymphangiogenesis in neonatal skin and mesentery, and mount weaker VEGF-C-induced cornea lymphangiogenesis. In vitro, human lymphatic EC with AIP1 siRNA knockdown, retinal EC and lymphatic EC isolated from AIP1-KO all show attenuated VEGF-C-induced VEGFR-3 signaling. Mechanistically, we demonstrate that AIP1 via <italic>vegfr-3</italic>
-specific <italic>miR-1236</italic>
increases VEGFR-3 protein expression, and by directly binding to VEGFR-3 enhances VEGFR-3 endocytosis and stability.</p>
</sec>
<sec id="S3"><title>Conclusion</title>
<p id="P3">Our in vivo and in vitro results provide the first insight into the mechanism by which AIP1 mediates VEGFR-3-dependent angiogenic and lymphangiogenic signaling.</p>
</sec>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9505803</journal-id>
<journal-id journal-id-type="pubmed-jr-id">8623</journal-id>
<journal-id journal-id-type="nlm-ta">Arterioscler Thromb Vasc Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">Arterioscler. Thromb. Vasc. Biol.</journal-id>
<journal-title-group><journal-title>Arteriosclerosis, thrombosis, and vascular biology</journal-title>
</journal-title-group>
<issn pub-type="ppub">1079-5642</issn>
<issn pub-type="epub">1524-4636</issn>
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<article-meta><article-id pub-id-type="pmid">24407031</article-id>
<article-id pub-id-type="pmc">3952062</article-id>
<article-id pub-id-type="doi">10.1161/ATVBAHA.113.303053</article-id>
<article-id pub-id-type="manuscript">NIHMS559303</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>AIP1 mediates VEGFR-3-dependent angiogenic and lymphangiogenic responses</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Zhou</surname>
<given-names>Huanjiao Jenny</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Xiaodong</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Renjing</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Haifeng</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Yingdi</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Jin</surname>
<given-names>Yu</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liang</surname>
<given-names>Xiaoling</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lu</surname>
<given-names>Lin</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Xu</surname>
<given-names>Zhe</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
<xref rid="FN1" ref-type="author-notes">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Min</surname>
<given-names>Wang</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref rid="FN1" ref-type="author-notes">5</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Interdepartmental Program in Vascular Biology and Therapeutics Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520</aff>
<aff id="A2"><label>2</label>
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China</aff>
<aff id="A3"><label>3</label>
Diseases of the Aorta Lab, Center for the Endothelium, Vascular Biology Program, Centenary Institute and University of Sydney, Sydney, Australia</aff>
<aff id="A4"><label>4</label>
Department of Ophthalmology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou. 510010. China</aff>
<author-notes><corresp id="FN1"><label>5</label>
Corresponding author: Dr. Wang Min, Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520. Tel: 203-785-6047; Fax: 203-737-2293; <email>wang.min@yale.edu</email>
and Dr. Zhe Xu at <email>oculistxuzhe@163.com</email>
</corresp>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>4</day>
<month>3</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>09</day>
<month>1</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="ppub"><month>3</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>3</month>
<year>2015</year>
</pub-date>
<volume>34</volume>
<issue>3</issue>
<fpage>603</fpage>
<lpage>615</lpage>
<pmc-comment>elocation-id from pubmed: 10.1161/ATVBAHA.113.303053</pmc-comment>
<abstract><sec id="S1"><title>Objective</title>
<p id="P1">To investigate the novel function of AIP1 in VEGFR-3 signaling, and VEGFR-3-dependent angiogenesis and lymphangiogenesis.</p>
</sec>
<sec id="S2"><title>Approach/Results</title>
<p id="P2">AIP1, a signaling scaffold protein, is highly expressed in the vascular endothelium. We have previously reported that AIP1 functions as an endogenous inhibitor in pathological angiogenesis by blocking VEGFR-2 activity. Surprisingly, here we observe that mice with a global deletion of AIP1 (AIP1-KO) exhibit reduced retinal angiogenesis with less sprouting and fewer branches. Vascular endothelial cell (but not neuronal)-specific deletion of AIP1 causes similar defects in retinal angiogenesis. The reduced retinal angiogenesis correlates with reduced expression in VEGFR-3 despite increased VEGFR-2 levels in AIP1-KO retinas. Consistent with the reduced expression of VEGFR-3, AIP1-KO mice show delayed developmental lymphangiogenesis in neonatal skin and mesentery, and mount weaker VEGF-C-induced cornea lymphangiogenesis. In vitro, human lymphatic EC with AIP1 siRNA knockdown, retinal EC and lymphatic EC isolated from AIP1-KO all show attenuated VEGF-C-induced VEGFR-3 signaling. Mechanistically, we demonstrate that AIP1 via <italic>vegfr-3</italic>
-specific <italic>miR-1236</italic>
increases VEGFR-3 protein expression, and by directly binding to VEGFR-3 enhances VEGFR-3 endocytosis and stability.</p>
</sec>
<sec id="S3"><title>Conclusion</title>
<p id="P3">Our in vivo and in vitro results provide the first insight into the mechanism by which AIP1 mediates VEGFR-3-dependent angiogenic and lymphangiogenic signaling.</p>
</sec>
</abstract>
<kwd-group><kwd>AIP1</kwd>
<kwd>VEGF</kwd>
<kwd>VEGFR-2</kwd>
<kwd>VEGFR-3</kwd>
<kwd>lymphangiogenesis</kwd>
<kwd>vascular biology</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Australie</li>
<li>République populaire de Chine</li>
<li>États-Unis</li>
</country>
<region><li>Connecticut</li>
<li>Guangdong</li>
<li>Nouvelle-Galles du Sud</li>
</region>
<settlement><li>Jiangmen</li>
<li>Sydney</li>
</settlement>
</list>
<tree><noCountry><name sortKey="Xu, Zhe" sort="Xu, Zhe" uniqKey="Xu Z" first="Zhe" last="Xu">Zhe Xu</name>
</noCountry>
<country name="États-Unis"><region name="Connecticut"><name sortKey="Zhou, Huanjiao Jenny" sort="Zhou, Huanjiao Jenny" uniqKey="Zhou H" first="Huanjiao Jenny" last="Zhou">Huanjiao Jenny Zhou</name>
</region>
<name sortKey="Chen, Xiaodong" sort="Chen, Xiaodong" uniqKey="Chen X" first="Xiaodong" last="Chen">Xiaodong Chen</name>
<name sortKey="Jin, Yu" sort="Jin, Yu" uniqKey="Jin Y" first="Yu" last="Jin">Yu Jin</name>
<name sortKey="Min, Wang" sort="Min, Wang" uniqKey="Min W" first="Wang" last="Min">Wang Min</name>
<name sortKey="Wang, Yingdi" sort="Wang, Yingdi" uniqKey="Wang Y" first="Yingdi" last="Wang">Yingdi Wang</name>
<name sortKey="Zhang, Haifeng" sort="Zhang, Haifeng" uniqKey="Zhang H" first="Haifeng" last="Zhang">Haifeng Zhang</name>
</country>
<country name="République populaire de Chine"><region name="Guangdong"><name sortKey="Zhou, Huanjiao Jenny" sort="Zhou, Huanjiao Jenny" uniqKey="Zhou H" first="Huanjiao Jenny" last="Zhou">Huanjiao Jenny Zhou</name>
</region>
<name sortKey="Chen, Xiaodong" sort="Chen, Xiaodong" uniqKey="Chen X" first="Xiaodong" last="Chen">Xiaodong Chen</name>
<name sortKey="Liang, Xiaoling" sort="Liang, Xiaoling" uniqKey="Liang X" first="Xiaoling" last="Liang">Xiaoling Liang</name>
<name sortKey="Lu, Lin" sort="Lu, Lin" uniqKey="Lu L" first="Lin" last="Lu">Lin Lu</name>
</country>
<country name="Australie"><region name="Nouvelle-Galles du Sud"><name sortKey="Liu, Renjing" sort="Liu, Renjing" uniqKey="Liu R" first="Renjing" last="Liu">Renjing Liu</name>
</region>
</country>
</tree>
</affiliations>
</record>
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