DISTINCT ROLES FOR Cx37 AND Cx40 IN REGULATING VASCULAR RESPONSES FOLLOWING ISCHEMIA

Persistent Link:
http://hdl.handle.net/10150/195758
Title:
DISTINCT ROLES FOR Cx37 AND Cx40 IN REGULATING VASCULAR RESPONSES FOLLOWING ISCHEMIA
Author:
Fang, Jennifer Shea-Ying
Issue Date:
2010
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:
Gap junctions are intercellular channels that permit passage of electrical and chemical signals between neighbouring cells. Vascular endothelium typically co-expresses Cx37 and Cx40, but may downregulate its expression of Cx37 (and upregulate Cx43) in response to changes in flow. The specific regulatory roles mediated by vascular endothelial connexins, and the consequences of altered connexin expression, remain unclear. In this study, we hypothesized that Cx37 and Cx40 regulate distinct vascular responses. We further hypothesize that Cx37 is predominantly involved in vascular growth control, whereas vascular growth is not affected by ablation of Cx40 expression. We show herein that Cx37, but not Cx40 or Cx43, suppresses growth of a highly-proliferative cancer cell line by inducing G1 cell cycle accumulation. We further show that Cx37-deficient mice, lacking Cx37's putative growth inhibitory effect on the vasculature, exhibit a more extensive native and post-ischemic collateral circulation, and greater ischemia-induced microvascular density. In addition, Cx37-/- mice demonstrate a functional improvement in recovery over wild-type animals in two models of hindlimb ischemia. By contrast, Cx40-/- mice fail to recover distal limb flow following unilateral hindlimb ischemia, resulting in necrosis. Long-term angiotensin II antagonism normalized post-ischemic hindlimb bloodflow, reduced macrophage infiltration, and delayed (but did not reverse) the necrotic phenotype of these animals. In summary, we show a distinct role for each of the endothelial connexins, Cx37 and Cx40, in regulating post-ischemic vascular responses.
Type:
text; Electronic Dissertation
Keywords:
Angiogenesis; Collateral; Connexin; Gap Junction; Ischemia; Vascular Remodeling
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Physiological Sciences; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Burt, Janis M.; Simon, Alexander M.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleDISTINCT ROLES FOR Cx37 AND Cx40 IN REGULATING VASCULAR RESPONSES FOLLOWING ISCHEMIAen_US
dc.creatorFang, Jennifer Shea-Yingen_US
dc.contributor.authorFang, Jennifer Shea-Yingen_US
dc.date.issued2010en_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.abstractGap junctions are intercellular channels that permit passage of electrical and chemical signals between neighbouring cells. Vascular endothelium typically co-expresses Cx37 and Cx40, but may downregulate its expression of Cx37 (and upregulate Cx43) in response to changes in flow. The specific regulatory roles mediated by vascular endothelial connexins, and the consequences of altered connexin expression, remain unclear. In this study, we hypothesized that Cx37 and Cx40 regulate distinct vascular responses. We further hypothesize that Cx37 is predominantly involved in vascular growth control, whereas vascular growth is not affected by ablation of Cx40 expression. We show herein that Cx37, but not Cx40 or Cx43, suppresses growth of a highly-proliferative cancer cell line by inducing G1 cell cycle accumulation. We further show that Cx37-deficient mice, lacking Cx37's putative growth inhibitory effect on the vasculature, exhibit a more extensive native and post-ischemic collateral circulation, and greater ischemia-induced microvascular density. In addition, Cx37-/- mice demonstrate a functional improvement in recovery over wild-type animals in two models of hindlimb ischemia. By contrast, Cx40-/- mice fail to recover distal limb flow following unilateral hindlimb ischemia, resulting in necrosis. Long-term angiotensin II antagonism normalized post-ischemic hindlimb bloodflow, reduced macrophage infiltration, and delayed (but did not reverse) the necrotic phenotype of these animals. In summary, we show a distinct role for each of the endothelial connexins, Cx37 and Cx40, in regulating post-ischemic vascular responses.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectAngiogenesisen_US
dc.subjectCollateralen_US
dc.subjectConnexinen_US
dc.subjectGap Junctionen_US
dc.subjectIschemiaen_US
dc.subjectVascular Remodelingen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.chairBurt, Janis M.en_US
dc.contributor.chairSimon, Alexander M.en_US
dc.contributor.committeememberBoitano, Scotten_US
dc.contributor.committeememberNelson, Marken_US
dc.identifier.proquest11380en_US
dc.identifier.oclc752261246en_US
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