# Stroke in females with metabolic syndrome, a vascular perspective

> **NIH NIH R01** · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · 2020 · $303,553

## Abstract

Metabolic syndrome (MetS) is associated with an increased risk of stroke and poor outcome, yet
the mechanisms underlying this health predicament are unclear. Hypertension, a revolving
complication of MetS, disrupts cerebral vasoregulatory mechanisms and increases the
susceptibility of the brain to ischemic injury, is more prevalent in postmenopausal women.
Emerging evidence suggests that patients with MetS are associated with poor collateral status
during acute ischemic stroke. Our recent data showed that female mice with MetS exhibited
poor collateral status during stroke and larger stroke size after MCAO. Mice with MetS also
have reduced blood flow in penetrating arterioles and impairment in microvascular flow
dynamics. Ample evidence links diabetes to impaired vasodilation that is attributable to reduced
eNOS phosphorylation; however, the role of eNOS in mediating pial and penetrating arteriole
flow after stroke has never been properly addressed. Given the known effect of estrogen on
increasing eNOS activity and the fact that T2DM associated reduction in estrogen, it is unclear
whether the impaired collateral flow in the aged female mice with MetS is attributed to reduced
eNOS activity. Clinical evidence also suggests that MetS induced-hypercoagulability has a
greater impact on adverse vascular events in women than in men including the risk of ischemic
stroke. Extracellular vesicles (EV) and exosomes are recognized as key players in
cardiovascular and metabolic diseases, and platelet-derived EVs are particularly important in
mediating thrombotic events that can potentiate the risk of stroke and worsen blood flow. The
proposed study will investigate the causal relationship between reduced blood perfusion and
impaired eNOS as well as EV-mediated increase in platelet activation/coagulation in
reproductively senescent female mice with MetS. Cutting-edge technology including Doppler
Optical Coherence Tomography and Multiphoton Laser Scanning Microscopy will be employed
to detect blood flow dynamics in pial and penetrating arterioles as well as capillary vessels, clot
and platelet-leukocyte aggregates formation before and after stroke. Transgenic knock-in mice
expressing phosphomimetic eNOS will be used to ascertain the role of vasodilation in regulating
collateral flow in db/db females. The role of EVs in increasing clotting and causing collateral
failure will be tested in vivo by injecting Isolated EVs into the jugular vein of MetS and normal
mice. The proposed studies in this application will provide insights into the complex biology of
poor blood perfusion especially in women with MetS with proof-of-concept data for future
development of collateral therapy.

## Key facts

- **NIH application ID:** 9852465
- **Project number:** 5R01NS102886-03
- **Recipient organization:** NORTHERN CALIFORNIA INSTITUTE/RES/EDU
- **Principal Investigator:** JIALING LIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $303,553
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852465

## Citation

> US National Institutes of Health, RePORTER application 9852465, Stroke in females with metabolic syndrome, a vascular perspective (5R01NS102886-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852465. Licensed CC0.

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