The project has yielded several key observations that significantly advance our understanding of hypertension and its underlying mechanisms.
While performing a cohort study and recruiting patients, we focused our mechanistic approaches on identifying key regulators of immune activation in models of hypertension. Early findings identified microRNA-214 (miR-214) as a major driver of arterial stiffness and vascular ageing. Through the use of animal models, cell cultures, and human samples, we demonstrated that T cell-derived miR-214 directs immune cells to the perivascular fat, inducing inflammation and structural damage. Elevated miR-214 levels in hypertensive patients underscore its potential as both a biomarker and therapeutic target. This work clarifies the role of immune responses in contributing to vascular changes in hypertension and identifies a potential regulatory target.
Another major outcome was establishing a causal link between gum inflammation, periodontitis, and high blood pressure. Using preclinical models, genetic studies, clinical trials, and meta-analyses, we demonstrated that periodontal inflammation contributes to the development of hypertension and that its treatment improves blood pressure control in patients with difficult-to-treat hypertension. These clinically relevant findings attracted strong interest from both the public and medical communities, receiving broad media coverage and widespread discussion across professional and social platforms.
We conducted large-scale genetic analyses in over 750,000 individuals, revealing strong associations between immune cells, particularly lymphocytes, monocytes, and neutrophils and blood pressure. Mendelian randomisation provided genetic evidence of the causal relationship between lymphocyte function and blood pressure regulation in humans. These findings support the central hypothesis that immune dysregulation drives hypertension. The scale and clarity of the evidence underscore the key role of immune pathways in regulating blood pressure at the population level.
Clinical studies of newly diagnosed hypertensive patients included detailed assessments of blood pressure, vascular stiffness, endothelial function, and immune and proteomic profiles. Machine learning identified distinct hypertension subtypes linked to specific immune markers: IL-17, IL-33, IFN-γ, IL-7, IL-15, SPINK6, and immune cells such as Th17 and CD28-null T cells. These profiles enable improved patient stratification based on inflammatory characteristics.
Basic mechanistic studies explored cytokine-driven T cell responses. Stimulation with IL-7 and IL-15 enhanced T cell survival and proliferation, activating calcium signalling pathways relevant to vascular injury. These cytokines emerged as promising therapeutic targets for modulating immune function in hypertension.
Further insights came from gene knockout models. Mice lacking IL-15RA exhibited reduced hypertension and vascular inflammation, while miR-214 deletion reduced fibrosis and improved vascular function despite elevated blood pressure. These findings demonstrate the direct involvement of immune pathways in the process of vascular damage.
An additional breakthrough was the identification of artery-brain circuits - neural-immune pathways linking the brain and arteries, that play roles in hypertension, atherosclerosis, and aneurysms. This finding opens up a new research area in neuroimmune regulation of cardiovascular disease. This was accompanied by studies identifying links between immune activation and specific brain centres, providing an additional link between hypertension and dementia.
Proteomic analysis of ~20,000 UK Biobank participants identified proteins associated with hypertension and cardiovascular outcomes. Participants clustered into five phenotypes based on protein profiles. Some normotensive individuals exhibited high inflammation-related risk, while hypertensives with strong lysosomal and inflammatory signatures had poorer outcomes. These findings support precision medicine approaches using immune and proteomic data for risk stratification and targeted care.
The project leveraged advanced technologies, single-cell RNA sequencing, high-density immunophenotyping, atomic force microscopy, and refined hypertension models. Findings were widely disseminated via peer-reviewed publications, international conferences, media, and social platforms. Collectively, InflammaTENSION has redefined hypertension as an immune-driven disease, uncovered key biomarkers and therapeutic targets, and laid the foundation for immune-based strategies in cardiovascular prevention and care.
