Soluble Epoxide Hydrolase Inhibition Attenuates Vascular Remodeling and Protects Against Cerebral Ischemia

Hdl Handle:
http://hdl.handle.net/10675.2/319928
Title:
Soluble Epoxide Hydrolase Inhibition Attenuates Vascular Remodeling and Protects Against Cerebral Ischemia
Authors:
Simpkins, Alexis Netis
Abstract:
Hypertension is linked to the incidence of cardiovascular events such as ischemic stroke due to several mechanisms, including vascular remodeling. The progression of vascular remodeling leads to increased arterial stiffness, plaque formation and rupture, and thrombosis, culminating in blockage of the arterial supply to the brain. A strategy to confer protection from hypertension linked cardiovascular events is inhibition of pathological remodeling. Notably, epoxyeicosatrienoic acids (EETs) modulate vascular smooth muscle cell (VSMC) proliferation and migration and vascular tone. However, their conversion by soluble epoxide hydrolase (SEH) enzyme to less active diols attenuates their protective properties. As a result, an alternative strategy to confer protection from the sequela of hypertension is SEH inhibition. Here we show that SEH inhibition and deletion of the gene responsible for the production of the SEH enzyme protects against pathological vascular remodeling in a model in which the endothelium is preserved via left carotid ligation. Interestingly, this protection was not observed in a model of arterial injury in which the femoral artery is denuded. This demonstrates that SEH antagonism has potential for protecting against pathological remodeling by an endothelium dependent mechanism. In line with this finding, we demonstrated that SEH inhibition restored the plasticity of carotid arteries in hypertensive rats with impaired responses to increases or decreases in flow. Importantly, we demonstrated that these protective properties of SEH inhibition were translatable to vascular protection from cerebral ischemia in an animal model of essential hypertension. Chronic SEH inhibition protected against cerebral ischemia in hypertensive rats by inhibiting vascular remodeling of the middle cerebral artery and increasing microvessel density. Interestingly, we also show that SEH inhibition is able to protect against cerebral ischemia without changing the structure of the vasculature of normotensive animals. In fact, we found that a potential for protection could be afforded by changes in the expression profile of genes involved in apoptosis, neurogenesis, and reactive oxygen species antagonism in models both of hypertension and normotension. The sum of these findings indicates that SEH inhibition has broad pharmacological potential for protecting against the occurrence and severity of ischemic stroke by mechanisms that are attributed to blocking the sequela of hypertension and neuroprotection.
Affiliation:
Department of Pharmacology and Toxicology
Issue Date:
May-2008
URI:
http://hdl.handle.net/10675.2/319928
Additional Links:
http://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/304403230?accountid=12365
Type:
Dissertation
Language:
en
Appears in Collections:
Department of Pharmacology and Toxicology Theses and Dissertations; Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorSimpkins, Alexis Netisen
dc.date.accessioned2014-06-06T02:20:15Z-
dc.date.available2014-06-06T02:20:15Z-
dc.date.issued2008-05-
dc.identifier.urihttp://hdl.handle.net/10675.2/319928-
dc.description.abstractHypertension is linked to the incidence of cardiovascular events such as ischemic stroke due to several mechanisms, including vascular remodeling. The progression of vascular remodeling leads to increased arterial stiffness, plaque formation and rupture, and thrombosis, culminating in blockage of the arterial supply to the brain. A strategy to confer protection from hypertension linked cardiovascular events is inhibition of pathological remodeling. Notably, epoxyeicosatrienoic acids (EETs) modulate vascular smooth muscle cell (VSMC) proliferation and migration and vascular tone. However, their conversion by soluble epoxide hydrolase (SEH) enzyme to less active diols attenuates their protective properties. As a result, an alternative strategy to confer protection from the sequela of hypertension is SEH inhibition. Here we show that SEH inhibition and deletion of the gene responsible for the production of the SEH enzyme protects against pathological vascular remodeling in a model in which the endothelium is preserved via left carotid ligation. Interestingly, this protection was not observed in a model of arterial injury in which the femoral artery is denuded. This demonstrates that SEH antagonism has potential for protecting against pathological remodeling by an endothelium dependent mechanism. In line with this finding, we demonstrated that SEH inhibition restored the plasticity of carotid arteries in hypertensive rats with impaired responses to increases or decreases in flow. Importantly, we demonstrated that these protective properties of SEH inhibition were translatable to vascular protection from cerebral ischemia in an animal model of essential hypertension. Chronic SEH inhibition protected against cerebral ischemia in hypertensive rats by inhibiting vascular remodeling of the middle cerebral artery and increasing microvessel density. Interestingly, we also show that SEH inhibition is able to protect against cerebral ischemia without changing the structure of the vasculature of normotensive animals. In fact, we found that a potential for protection could be afforded by changes in the expression profile of genes involved in apoptosis, neurogenesis, and reactive oxygen species antagonism in models both of hypertension and normotension. The sum of these findings indicates that SEH inhibition has broad pharmacological potential for protecting against the occurrence and severity of ischemic stroke by mechanisms that are attributed to blocking the sequela of hypertension and neuroprotection.en
dc.language.isoenen
dc.relation.urlhttp://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/304403230?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.-
dc.subjectHypertensionen
dc.subjectVascular Remodelingen
dc.subjectIschemic Strokeen
dc.titleSoluble Epoxide Hydrolase Inhibition Attenuates Vascular Remodeling and Protects Against Cerebral Ischemiaen
dc.typeDissertationen
dc.contributor.departmentDepartment of Pharmacology and Toxicology-
dc.description.advisorImig, John; Inscho, Edwarden
dc.description.committeeFulton, David; Pollock, Jennifer; Reed, Guyen
dc.description.degreeDoctor of Philosophy (Ph.D.)-
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