Contrasting Defects in Lymphangiogenic Remodeling and Lymphangiogenesis Revealed in Angiopoietin-2 Deficient and Vegfc Hemizygous Mice

Persistent Link:
http://hdl.handle.net/10150/195639
Title:
Contrasting Defects in Lymphangiogenic Remodeling and Lymphangiogenesis Revealed in Angiopoietin-2 Deficient and Vegfc Hemizygous Mice
Author:
Dellinger, Mike
Issue Date:
2008
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Despite recent advances in lymphology, the molecular mechanisms regulating the development of the lymphatic system have not been fully delineated. Here I show that the growth factors Angiopoietin-2 (Ang2) and Vascular endothelial growth factor-c (Vegfc) serve distinct roles in the development of the lymphatic system.Adult Ang2-/- mice exhibit dermal lymphatic hypoplasia, abnormal smooth muscle cell (SMC) coverage of initial lymphatic vessels, and a severe deficiency of collecting lymphatic vessels. To determine whether these abnormalities were due to defects in the remodeling of the lymphatic vasculature, I characterized this process in Ang2-/- mice. Indeed, lymphatic vessels in the skin of Ang2-/- pups prematurely recruited SMCs and did not mature into collecting vessels during the remodeling stage of lymphatic development. In contrast, Ang2 knockout Ang1 knock-in mice did develop a hierarchal lymphatic vasculature, suggesting that activation of Tie-2 is required for normal lymphatic development. To further delineate the molecular mechanisms regulating lymphatic development, I also characterized Chylous ascites-3 (Chy-3) mice, a strain missing cytobands 8A4 to 8B3 from one copy of chromosome 8. Real-time PCR using genomic DNA demonstrated that the lymphangiogenesis gene, Vegfc, was included in the deleted region. All of the key components of a normal lymphatic network had developed in Chy-3 mice; however, the number of lymphatic vessels was reduced. Although the patterning of lymphatic vasculature in Chy-3 mice was altered, the architecture of the blood vasculature appeared normal. Ang2-/- and Chy-3 mice are grossly indistinguishable from one another; however, their underlying lymphatic defects are dramatically different. Ang2-/- mice exhibit defects in lymphangiogenic remodeling and lymphangiogenesis, whereas Chy-3 mice show a reduced capacity for lymphangiogenesis. I propose that Ang2 maintains lymphatic vessel plasticity by preventing SMC-lymphatic vessel associations so maturation can occur and facilitates lymphangiogenesis in the presence of Vegfc. This is analogous to Ang2's function on the blood vasculature where it is thought to destabilize SMC-blood vessel interactions and facilitate hemangiogenesis in the presence of Vegfa.Taken together, these findings further delineate the development of the lymphatic system and could provide translational clues relevant to the pathogenesis and treatment of clinical disorders of the lymphatic system.
Type:
text; Electronic Dissertation
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Molecular & Cellular Biology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Erickson, Robert P.
Committee Chair:
Erickson, Robert P.

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleContrasting Defects in Lymphangiogenic Remodeling and Lymphangiogenesis Revealed in Angiopoietin-2 Deficient and Vegfc Hemizygous Miceen_US
dc.creatorDellinger, Mikeen_US
dc.contributor.authorDellinger, Mikeen_US
dc.date.issued2008en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractDespite recent advances in lymphology, the molecular mechanisms regulating the development of the lymphatic system have not been fully delineated. Here I show that the growth factors Angiopoietin-2 (Ang2) and Vascular endothelial growth factor-c (Vegfc) serve distinct roles in the development of the lymphatic system.Adult Ang2-/- mice exhibit dermal lymphatic hypoplasia, abnormal smooth muscle cell (SMC) coverage of initial lymphatic vessels, and a severe deficiency of collecting lymphatic vessels. To determine whether these abnormalities were due to defects in the remodeling of the lymphatic vasculature, I characterized this process in Ang2-/- mice. Indeed, lymphatic vessels in the skin of Ang2-/- pups prematurely recruited SMCs and did not mature into collecting vessels during the remodeling stage of lymphatic development. In contrast, Ang2 knockout Ang1 knock-in mice did develop a hierarchal lymphatic vasculature, suggesting that activation of Tie-2 is required for normal lymphatic development. To further delineate the molecular mechanisms regulating lymphatic development, I also characterized Chylous ascites-3 (Chy-3) mice, a strain missing cytobands 8A4 to 8B3 from one copy of chromosome 8. Real-time PCR using genomic DNA demonstrated that the lymphangiogenesis gene, Vegfc, was included in the deleted region. All of the key components of a normal lymphatic network had developed in Chy-3 mice; however, the number of lymphatic vessels was reduced. Although the patterning of lymphatic vasculature in Chy-3 mice was altered, the architecture of the blood vasculature appeared normal. Ang2-/- and Chy-3 mice are grossly indistinguishable from one another; however, their underlying lymphatic defects are dramatically different. Ang2-/- mice exhibit defects in lymphangiogenic remodeling and lymphangiogenesis, whereas Chy-3 mice show a reduced capacity for lymphangiogenesis. I propose that Ang2 maintains lymphatic vessel plasticity by preventing SMC-lymphatic vessel associations so maturation can occur and facilitates lymphangiogenesis in the presence of Vegfc. This is analogous to Ang2's function on the blood vasculature where it is thought to destabilize SMC-blood vessel interactions and facilitate hemangiogenesis in the presence of Vegfa.Taken together, these findings further delineate the development of the lymphatic system and could provide translational clues relevant to the pathogenesis and treatment of clinical disorders of the lymphatic system.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMolecular & Cellular Biologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorErickson, Robert P.en_US
dc.contributor.chairErickson, Robert P.en_US
dc.contributor.committeememberWitte, Marlysen_US
dc.contributor.committeememberPatterson, Bruceen_US
dc.contributor.committeememberNagy, Lisaen_US
dc.contributor.committeememberWeinert, Teden_US
dc.identifier.proquest2772en_US
dc.identifier.oclc659749803en_US
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