Modulation of the Blood-Brain Barrier During Hypertension Development

Persistent Link:
http://hdl.handle.net/10150/196090
Title:
Modulation of the Blood-Brain Barrier During Hypertension Development
Author:
Hom, Sharon
Issue Date:
2006
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:
Hypertension is involved in the exacerbation of stroke. Increased blood-brain barrier (BBB) permeability and cerebral edema formation are potentially lethal complications of cerebral infarction. It is unclear how BBB tight junction (TJ), ion transporter, and protein kinase C (PKC) signaling pathway proteins critical for maintaining brain homeostasis contribute to cerebral infarction during hypertension development. The hypothesis of this study is that hypertension leads to molecular changes in the BBB which predispose the brain to increased cerebral infarct damage following ischemic stroke. Studies were undertaken to investigate the effect of hypertension development on (1) physiological parameters of the spontaneously hypertensive rat (SHR) and on the expression levels of BBB TJ, ion transporter, and PKC proteins potentially involved in ischemia-induced infarct damage; (2) ischemia-induced infarct volume following permanent middle cerebral artery occlusion (MCAO); and (3) the effect of inhibition of Na+/H+ exchanger isoform 1 (NHE-1) on ischemia-induced infarct volume following permanent MCAO in hypertensive SHR (15 weeks). Early hypertension development was determined in SHR and compared to normotensive, age-matched Wistar-Kyoto (WKY) rats at 5 (pre-hypertension), 10 (early stage hypertension), and 15 (later stage hypertension) weeks of age. Characterization of BBB TJ and ion transporter proteins known to contribute to edema and fluid volume changes in the brain show differential protein expression patterns during hypertension development. Western blot analysis of TJ zonula occludens-2 (ZO-2) showed decreased expression while ion transporter, NHE-1 was markedly increased in hypertensive SHR (15 weeks) compared to age-matched controls. Hypertensive SHR (10 and 15 weeks) showed greatly increased necrotic volume with impaired neurological deficits and edema formation. Increased NHE-1 expression in hypertensive SHR (15 week) suggests a potential role for this ion transporter in the promotion of ischemic brain injury. Selective inhibition of NHE-1 using 5-(N,N-Dimethyl)amiloride (DMA) showed significant attenuation in ischemia-induced infarct volume in hypertensive SHR following MCAO. These data suggest a novel role for NHE-1 at the BBB/neurovascular unit in the regulation of ischemia-induced infarct volume in hypertensive SHR suggesting that modulation of NHE-1 may be a factor important in the potentiation of MCAO infarct size and a novel therapeutic target in the prevention of ischemic stroke.
Type:
text; Electronic Dissertation
Keywords:
Physiological Sciences
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Physiological Sciences; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Davis, Thomas P
Committee Chair:
Davis, Thomas P

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleModulation of the Blood-Brain Barrier During Hypertension Developmenten_US
dc.creatorHom, Sharonen_US
dc.contributor.authorHom, Sharonen_US
dc.date.issued2006en_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.abstractHypertension is involved in the exacerbation of stroke. Increased blood-brain barrier (BBB) permeability and cerebral edema formation are potentially lethal complications of cerebral infarction. It is unclear how BBB tight junction (TJ), ion transporter, and protein kinase C (PKC) signaling pathway proteins critical for maintaining brain homeostasis contribute to cerebral infarction during hypertension development. The hypothesis of this study is that hypertension leads to molecular changes in the BBB which predispose the brain to increased cerebral infarct damage following ischemic stroke. Studies were undertaken to investigate the effect of hypertension development on (1) physiological parameters of the spontaneously hypertensive rat (SHR) and on the expression levels of BBB TJ, ion transporter, and PKC proteins potentially involved in ischemia-induced infarct damage; (2) ischemia-induced infarct volume following permanent middle cerebral artery occlusion (MCAO); and (3) the effect of inhibition of Na+/H+ exchanger isoform 1 (NHE-1) on ischemia-induced infarct volume following permanent MCAO in hypertensive SHR (15 weeks). Early hypertension development was determined in SHR and compared to normotensive, age-matched Wistar-Kyoto (WKY) rats at 5 (pre-hypertension), 10 (early stage hypertension), and 15 (later stage hypertension) weeks of age. Characterization of BBB TJ and ion transporter proteins known to contribute to edema and fluid volume changes in the brain show differential protein expression patterns during hypertension development. Western blot analysis of TJ zonula occludens-2 (ZO-2) showed decreased expression while ion transporter, NHE-1 was markedly increased in hypertensive SHR (15 weeks) compared to age-matched controls. Hypertensive SHR (10 and 15 weeks) showed greatly increased necrotic volume with impaired neurological deficits and edema formation. Increased NHE-1 expression in hypertensive SHR (15 week) suggests a potential role for this ion transporter in the promotion of ischemic brain injury. Selective inhibition of NHE-1 using 5-(N,N-Dimethyl)amiloride (DMA) showed significant attenuation in ischemia-induced infarct volume in hypertensive SHR following MCAO. These data suggest a novel role for NHE-1 at the BBB/neurovascular unit in the regulation of ischemia-induced infarct volume in hypertensive SHR suggesting that modulation of NHE-1 may be a factor important in the potentiation of MCAO infarct size and a novel therapeutic target in the prevention of ischemic stroke.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectPhysiological Sciencesen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePhysiological Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorDavis, Thomas Pen_US
dc.contributor.chairDavis, Thomas Pen_US
dc.contributor.committeememberLynch, Ronald M.en_US
dc.contributor.committeememberParsons, L. Claireen_US
dc.contributor.committeememberStamer, W. Danielen_US
dc.contributor.committeememberVanderah, Todd W.en_US
dc.identifier.proquest1797en_US
dc.identifier.oclc659747560en_US
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