Date of Award

2026

Degree Name

Biomedical Research

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Dr. Ji Chen Bihl

Second Advisor

Dr. Nalini Santanam

Third Advisor

Dr. Richard Egleton

Fourth Advisor

Dr. Jinju Wang

Fifth Advisor

Dr. Yonke Lu

Sixth Advisor

Dr. Alip Borthakur

Abstract

Type 2 diabetes mellitus (T2DM) is a major risk factor for ischemic stroke (IS) and is characterized by chronic hyperglycemia and adipose tissue dysfunction. Adipose tissue releases exosomes that function as systemic signaling mediators and may contribute to vascular injury. Although diabetes is associated with worsened stroke outcomes, the mechanisms linking adipose dysfunction to cerebrovascular damage remain incompletely understood. This dissertation tested the hypothesis that hyperglycemic adipocyte-derived exosomes (Ad-EXs) exacerbate brain microvascular endothelial cell (BMEC) injury during ischemic stroke by promoting oxidative stress, lipid peroxidation, and mitochondrial dysfunction. Exosomes were isolated from adipocytes cultured under normal- or high-glucose conditions and applied to human BMECs subjected to hypoxia/reoxygenation injury in vitro. Endothelial function, oxidative stress, and mitochondrial integrity were evaluated. In complementary in vivo studies, exosomes isolated from control or diabetic (db/db) mice were administered to mice subjected to middle cerebral artery occlusion, and neurological function was assessed. Hyperglycemic Ad-EXs significantly impaired endothelial viability, migration, and angiogenic capacity compared to control exosomes. These effects were associated with increased reactive oxygen species production, enhanced lipid peroxidation, and disrupted mitochondrial function. In vivo, diabetic Ad-EXs crossed the blood-brain barrier, localized to peri-infarct endothelial cells, and worsened sensorimotor deficits following ischemic stroke. Collectively, these findings demonstrate that hyperglycemic adipocyte-derived exosomes aggravate ischemic cerebrovascular injury by inducing oxidative stress mediated mitochondrial dysfunction. This work identifies a novel adipose-brain vascular signaling axis that mechanistically links diabetes to poor stroke outcomes and highlights Ad-EXs as potential therapeutic targets in diabetic ischemic stroke.

Subject(s)

Neurosciences.

Cytology.

Molecular biology.

Endothelial cells.

Oxidative stress.

Type 2 diabetes.

Diabetes.

Cerebral ischemia.

Cerebrovascular disease.

Mitochondria -- Physiology.

Hyperglycemia.

Adipose tissues.

Blood-vessels.

Mitochondria -- Pathophysiology.

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