Persistent Link:
http://hdl.handle.net/10150/337290
Title:
Role Of Connexins In Post-Ischemic Vascular Remodeling
Author:
Good, Miranda Elizabeth
Issue Date:
2014
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:
Connexins are a family of gene products sharing a similar topology that mediate transmembrane and intercellular diffusion of ions and small molecules through hemichannels (HCs) and gap junction channels (GJCs), respectively, and participate in intracellular signaling through protein-protein interaction. Connexin 37 (Cx37) and Cx40 are co-expressed by endothelial cells, suggesting a unique role for each connexin in regulating cellular function. Through gene knockout studies in mice, Cx37 was found to regulate vascular cell proliferation while Cx40 regulates conduction of upstream vasomotor signals and leukocyte infiltration. The unique functions of Cx37 and Cx40 result in contrasting effects of ischemic injury in mice lacking expression of either Cx37 or Cx40 genes. Cx37 knockout mice (Cx37-/-) have significantly improved recovery due to an increase in both vasculogenesis and angiogenic processes. In the current studies, the mechanism by which Cx37 mediates cellular proliferation is explored by examining the role of functional GJCs and HCs. Channel function is necessary, but HC function is not sufficient for Cx37-mediated suppression of proliferation. These results suggest that Cx37 requires a competent GJC that supports a specific conformation of the carboxyl terminus that is able to interact with necessary growth regulatory protein(s). Conversely, Cx40-/- mice have reduced angiogenic and arteriogenic processes and impaired post-ischemic recovery. In the current study, we explored the inflammatory response following the femoral artery ligation (FAL) surgery, in wildtype (WT) and Cx40-/- mice. Cx40-/- mice had an excessive infiltration of activated neutrophils to the ischemic gastrocnemius muscle and a prolonged presence of activated macrophages. We depleted mice of circulating neutrophils during the induction of ischemia to evaluate if the excessive infiltration of neutrophils impaired recovery and found no improvement in post-ischemic recovery in either WT or Cx40-/- mice. These data indicate that, although Cx40-/- mice have a pro-inflammatory state that results in an excessive and prolonged presence of leukocytes post-ischemia, reduction of acute leukocyte infiltration does not improve post-ischemic recovery. Additional information is necessary to determine the mechanisms by which Cx37 and Cx40, individually or in concert with each other, regulate endothelial cell function and arterial vascular response to ischemic injury.
Type:
text; Electronic Dissertation
Keywords:
Connexin 40; Ischemia; Proliferation; Physiological Sciences; Connexin 37
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Physiological Sciences
Degree Grantor:
University of Arizona
Advisor:
Burt, Janis M.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleRole Of Connexins In Post-Ischemic Vascular Remodelingen_US
dc.creatorGood, Miranda Elizabethen_US
dc.contributor.authorGood, Miranda Elizabethen_US
dc.date.issued2014-
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.abstractConnexins are a family of gene products sharing a similar topology that mediate transmembrane and intercellular diffusion of ions and small molecules through hemichannels (HCs) and gap junction channels (GJCs), respectively, and participate in intracellular signaling through protein-protein interaction. Connexin 37 (Cx37) and Cx40 are co-expressed by endothelial cells, suggesting a unique role for each connexin in regulating cellular function. Through gene knockout studies in mice, Cx37 was found to regulate vascular cell proliferation while Cx40 regulates conduction of upstream vasomotor signals and leukocyte infiltration. The unique functions of Cx37 and Cx40 result in contrasting effects of ischemic injury in mice lacking expression of either Cx37 or Cx40 genes. Cx37 knockout mice (Cx37-/-) have significantly improved recovery due to an increase in both vasculogenesis and angiogenic processes. In the current studies, the mechanism by which Cx37 mediates cellular proliferation is explored by examining the role of functional GJCs and HCs. Channel function is necessary, but HC function is not sufficient for Cx37-mediated suppression of proliferation. These results suggest that Cx37 requires a competent GJC that supports a specific conformation of the carboxyl terminus that is able to interact with necessary growth regulatory protein(s). Conversely, Cx40-/- mice have reduced angiogenic and arteriogenic processes and impaired post-ischemic recovery. In the current study, we explored the inflammatory response following the femoral artery ligation (FAL) surgery, in wildtype (WT) and Cx40-/- mice. Cx40-/- mice had an excessive infiltration of activated neutrophils to the ischemic gastrocnemius muscle and a prolonged presence of activated macrophages. We depleted mice of circulating neutrophils during the induction of ischemia to evaluate if the excessive infiltration of neutrophils impaired recovery and found no improvement in post-ischemic recovery in either WT or Cx40-/- mice. These data indicate that, although Cx40-/- mice have a pro-inflammatory state that results in an excessive and prolonged presence of leukocytes post-ischemia, reduction of acute leukocyte infiltration does not improve post-ischemic recovery. Additional information is necessary to determine the mechanisms by which Cx37 and Cx40, individually or in concert with each other, regulate endothelial cell function and arterial vascular response to ischemic injury.en_US
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectConnexin 40en_US
dc.subjectIschemiaen_US
dc.subjectProliferationen_US
dc.subjectPhysiological Sciencesen_US
dc.subjectConnexin 37en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorBurt, Janis M.en_US
dc.contributor.committeememberBurt, Janis M.en_US
dc.contributor.committeememberSimon, Alex M.en_US
dc.contributor.committeememberBoitano, Scott A.en_US
dc.contributor.committeememberBriehl, Margaret M.en_US
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