Mechanism of Vascular Dysfunction after Stroke in Postmenopausal Female

Project: Research project

Description

DESCRIPTION (provided by applicant): The mechanisms underlying increased stroke risk and stroke-related brain damage in postmenopausal females are poorly understood. We will test the hypothesis that loss of ovarian hormones following menopause exacerbates brain damage after stroke, due to loss of cerebrovascular endothelial protective mechanisms, rendering endothelial cells (ECs) in postmenopausal women highly susceptible to ischemic injury and endothelial dysfunction. We will use in-vivo optical imaging of vascular perfusion to assess EC function in vivo, and determine if loss of ovarian hormones after reproductive senescence (RS) in middle-aged, 16-month old female mice exacerbates EC injury and dysfunction, leading to perfusion deficit and worsening brain damage after middle cerebral artery occlusion (MCAO). Mechanistically, we will determine if post-ischemic endothelial injury and dysfunction in reproductively senescent mice are linked to reduced signaling by endothelium-derived cytochrome P450 (CYP) eicosanoids called epoxyeicosatrienoic acids (EETs). Using transgenic mice with endothelial-specific overexpression of EETs-synthetic enzyme CYP2J2 (Tie2-2J2) and EETs-metabolizing enzyme soluble epoxide hydrolase (Tie2-sEH), we will determine if EC injury, perfusion deficit and reduced endothelial cell function after stroke in RS female mice are linked to sEH upregulation and loss of EETs. We will also use mice with endothelial-specific deletion of signal transducer and activator of transcription-3 (Tie2- Cre/Flox-STAT3) to determine if sEH upregulation in RS females is linked to loss of STAT3 signaling in cerebrovascular endothelium. The proposed studies examine a mechanism of injury specifically induced in postmenopausal female vessels. Selective targeting of sEH may represent a therapeutic strategy specifically tailored to and particularly effective in postmenopausal females, an age group with the highest stroke rate and mortality. PUBLIC HEALTH RELEVANCE: Cardiovascular disease, including stroke, is the largest single cause of death among women worldwide. Despite recent recognition that mechanisms of stroke are different between men and women, no therapy currently exists that specifically targets stroke in women. We have identified a mechanism of injury specifically induced in female brain vessels after menopause, which may serve as a target for stroke therapy particularly effective in post-menopausal females.
StatusFinished
Effective start/end date4/1/113/31/16

Funding

  • National Institutes of Health: $336,875.00
  • National Institutes of Health: $336,875.00
  • National Institutes of Health: $336,875.00
  • National Institutes of Health: $333,507.00
  • National Institutes of Health: $325,085.00

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Blood Vessels
Stroke
Eicosanoids
Endothelial Cells
Wounds and Injuries
Acids
Perfusion
Brain
Endothelium
Up-Regulation
Hormones
Menopause
Epoxide Hydrolases
STAT3 Transcription Factor
Middle Cerebral Artery Infarction
Optical Imaging
Enzymes
Cytochrome P-450 Enzyme System
Transgenic Mice
Age Groups

ASJC

  • Medicine(all)
  • Neuroscience(all)