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Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice

Identifieur interne : 002767 ( Pmc/Corpus ); précédent : 002766; suivant : 002768

Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice

Auteurs : Michael Dellinger ; Robert Hunter ; Michael Bernas ; Nicholas Gale ; George Yancopoulos ; Robert Erickson ; Marlys Witte

Source :

RBID : PMC:2536689

Abstract

Molecular mechanisms regulating the remodeling of the lymphatic vasculature from an immature plexus of vessels to a hierarchal network of initial and collecting lymphatics are not well understood. One gene thought to be important for this process is Angiopoietin-2 (Ang-2). Ang2-/- mice have previously been reported to exhibit an abnormal lymphatic phenotype but the precise nature of the lymphatic defects and the underlying mechanisms have yet to be defined. Here we demonstrate by whole-mount immunofluorescence staining of ear skin and mesentery that lymphatic vessels in Ang2-/- mice fail to mature and do not exhibit a collecting vessel phenotype. Furthermore, dermal lymphatic vessels in Ang2-/- pups prematurely recruit smooth muscle cells and do not undergo proper postnatal remodeling. In contrast, Ang2 knockout Ang1 knock-in mice do develop a hierarchal lymphatic vasculature, suggesting that activation of Tie-2 is required for normal lymphatic development. Taken together, this work pinpoints a specific lymphatic defect of Ang2-/- mice and further defines the sequential steps in lymphatic vessel remodeling.


Url:
DOI: 10.1016/j.ydbio.2008.04.024
PubMed: 18514180
PubMed Central: 2536689

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PMC:2536689

Le document en format XML

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<p id="P1">Molecular mechanisms regulating the remodeling of the lymphatic vasculature from an immature plexus of vessels to a hierarchal network of initial and collecting lymphatics are not well understood. One gene thought to be important for this process is Angiopoietin-2 (Ang-2).
<italic>Ang2
<sup>-/-</sup>
</italic>
mice have previously been reported to exhibit an abnormal lymphatic phenotype but the precise nature of the lymphatic defects and the underlying mechanisms have yet to be defined. Here we demonstrate by whole-mount immunofluorescence staining of ear skin and mesentery that lymphatic vessels in
<italic>Ang2
<sup>-/-</sup>
</italic>
mice fail to mature and do not exhibit a collecting vessel phenotype. Furthermore, dermal lymphatic vessels in
<italic>Ang2
<sup>-/-</sup>
</italic>
pups prematurely recruit smooth muscle cells and do not undergo proper postnatal remodeling. In contrast,
<italic>Ang2</italic>
knockout
<italic>Ang1</italic>
knock-in mice do develop a hierarchal lymphatic vasculature, suggesting that activation of Tie-2 is required for normal lymphatic development. Taken together, this work pinpoints a specific lymphatic defect of
<italic>Ang2
<sup>-/-</sup>
</italic>
mice and further defines the sequential steps in lymphatic vessel remodeling.</p>
</div>
</front>
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<article-title>Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice</article-title>
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<name>
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<given-names>Michael</given-names>
</name>
<xref rid="A2" ref-type="aff">2</xref>
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<name>
<surname>Gale</surname>
<given-names>Nicholas</given-names>
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<name>
<surname>Yancopoulos</surname>
<given-names>George</given-names>
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<xref rid="A4" ref-type="aff">4</xref>
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<name>
<surname>Erickson</surname>
<given-names>Robert</given-names>
</name>
<xref rid="A1" ref-type="aff">1</xref>
<xref rid="A3" ref-type="aff">3</xref>
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<contrib contrib-type="author">
<name>
<surname>Witte</surname>
<given-names>Marlys</given-names>
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<aff id="A1">
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Department of Molecular and Cellular Biology, The University of Arizona, Tucson, AZ</aff>
<aff id="A2">
<label>2</label>
Department of Surgery, The University of Arizona, Tucson, AZ</aff>
<aff id="A3">
<label>3</label>
Department of Pediatrics, The University of Arizona, Tucson, AZ</aff>
<aff id="A4">
<label>4</label>
Regeneron Pharmaceuticals, Inc., Tarrytown, NY</aff>
<author-notes>
<corresp id="FN1">Corresponding author: Marlys Hearst Witte, MD, Professor of Surgery, University of Arizona College of Medicine, 1501 N. Campbell Avenue, Room 4406, P.O. Box 245200, Tucson, AZ USA 85724-5200, Telephone: 520-626-6118, Fax: 520-626-0822, e-mail:
<email>lymph@u.arizona.edu</email>
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<pub-date pub-type="nihms-submitted">
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<abstract>
<p id="P1">Molecular mechanisms regulating the remodeling of the lymphatic vasculature from an immature plexus of vessels to a hierarchal network of initial and collecting lymphatics are not well understood. One gene thought to be important for this process is Angiopoietin-2 (Ang-2).
<italic>Ang2
<sup>-/-</sup>
</italic>
mice have previously been reported to exhibit an abnormal lymphatic phenotype but the precise nature of the lymphatic defects and the underlying mechanisms have yet to be defined. Here we demonstrate by whole-mount immunofluorescence staining of ear skin and mesentery that lymphatic vessels in
<italic>Ang2
<sup>-/-</sup>
</italic>
mice fail to mature and do not exhibit a collecting vessel phenotype. Furthermore, dermal lymphatic vessels in
<italic>Ang2
<sup>-/-</sup>
</italic>
pups prematurely recruit smooth muscle cells and do not undergo proper postnatal remodeling. In contrast,
<italic>Ang2</italic>
knockout
<italic>Ang1</italic>
knock-in mice do develop a hierarchal lymphatic vasculature, suggesting that activation of Tie-2 is required for normal lymphatic development. Taken together, this work pinpoints a specific lymphatic defect of
<italic>Ang2
<sup>-/-</sup>
</italic>
mice and further defines the sequential steps in lymphatic vessel remodeling.</p>
</abstract>
<kwd-group>
<kwd>Ang2</kwd>
<kwd>Angpt2</kwd>
<kwd>Angiopoietin-2</kwd>
<kwd>Ang2 knockout mice</kwd>
<kwd>Angiopoietin-1</kwd>
<kwd>Tie2</kwd>
<kwd>lymphedema</kwd>
<kwd>lymphangiogenesis</kwd>
<kwd>lymphatic development</kwd>
<kwd>lymphatic remodeling</kwd>
</kwd-group>
<contract-num rid="HL1">R01 HL071206-04</contract-num>
<contract-sponsor id="HL1">National Heart, Lung, and Blood Institute : NHLBI</contract-sponsor>
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