Role of ER stress in vascular dysfunction and damage during hypertension

Wang, Yu (2025) Role of ER stress in vascular dysfunction and damage during hypertension. PhD thesis, University of Glasgow.

Abstract

Hypertension is a major risk factor for cardiovascular diseases and involves complex molecular mechanisms that are not fully understood. Recent evidence indicates that endoplasmic reticulum (ER) stress plays a crucial role in hypertension, particularly by affecting vascular function. This thesis explores the hypothesis that ER stress contributes to hypertension through mechanisms involving oxidative stress, calcium signalling dysfunction, and changes in microRNA (miRNA) expression. These processes can lead to increased vascular contractility, which may ultimately contribute to elevated blood pressure.

This study utilised both human vascular smooth muscle cells (VSMCs) and animal models to investigate the molecular mechanisms linking ER stress to hypertension. Using miRNA microarray analysis, 242 differentially expressed (DE) miRNAs were identified when comparing VSMCs from hypertensive (HT) individuals to those from normotensive(NT)individuals, each represented by one sample derived from three different individuals. These (DE) miRNAs were associated with key genes and proteins related to oxidative stress and calcium signalling, including Noxs, SOD2, catalase, and ER calcium channels, as determined through Ingenuity Pathway Analysis (IPA). Notably, ER stress induced by tunicamycin significantly altered the expression of oxidative stress markers (Noxs, SOD2,catalase) and calcium channels in HT VSMCs compared to NT VSMCs, indicating that ER stress regulates oxidative stress and potentially contributes to calcium signalling dysfunction.

Further insights were gained from studying a chronic Ang II-induced hypertensive mice model (LinA3). ER stress was found to specifically activate the PERK pathway, indicating selective ER stress activation in VSMCs under hypertensive conditions. In this model, oxidative stress was characterized by increased O2 -• generation, lipid peroxidation, irreversible protein oxidation, and altered antioxidants system of VSMCs compared to wild-type mice. The role of Nox4 in modulating the interaction between oxidative stress and ER stress was highlighted, as Nox4 deficiency led to changes in the expression of ER stress markers, including increased BIP and Chop in the kidneys of wild-type mice and increased PDI in the kidneys of LinA3 mice. These findings suggest a potential roleforNox4 in modulating ER stress in hypertension.

This study found that the pre-hypertensive factor endothelin-1 (ET-1) induces ER stress and that ER stress contributes to vascular hypercontractility, using spontaneously hypertensive rats (SHRSP) compared to normotensive Wistar Kyoto (WKY) rats. Our findings demonstrated elevated levels of ER stress in the hearts and VSMCs of SHRSP compared to normotensive controls, indicating a link between ER stress andhypertension.ET-1 was found to induce ER stress through both ETA and ETB receptors, leading to increased expression of ER stress markers such as ATF4, XBP1s, and BIP. Inhibition of ER stress resulted in reduced activation of the contractile machinery, establishing a connection between ER stress, calcium signalling dysfunction, and the enhanced contractile response observed in hypertension.

Lastly, in vivo treatment with the ER stress inhibitor 4-phenylbutyric acid(4PBA)in spontaneously hypertensive rats (SHR) demonstrated reduced blood pressure, improved endothelial function, and a tendency toward improved vascular structure. These findings suggest that ER stress is a critical mediator of vascular dysfunction and structural changes in hypertension and present ER stress inhibition as a potential therapeutic strategy for managing hypertension.

In conclusion, this thesis highlights the role of ER stress in mediating vascular dysfunction in hypertension, emphasizing its interactions with oxidative stress, calcium dysfunction, and the potential involvement of miRNA regulation. These findings lay the ground work for the development of novel therapeutic strategies targeting ER stress to treat hypertension.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from the China Scholarship Council.
• Subjects: R Medicine > R Medicine (General); R Medicine > RC Internal medicine
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Supervisor's Name: McBride, Dr. Martin, Touyz, Professor Rhian and Montezano, Dr. Augusto
• Date of Award: 2025
• Depositing User: Theses Team
• Unique ID: glathesis:2025-85582
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 10 Nov 2025 15:03
• Last Modified: 10 Nov 2025 15:09
• Thesis DOI: 10.5525/gla.thesis.85582
• URI: https://theses.gla.ac.uk/id/eprint/85582