Immunometabolic Dysregulation Driving Vascular Dysfunction Underlying Cardiovascular Disease

Introduction: Cardiovascular disease (CVD) is the leading cause of global mortality, driven by vascular dysfunction. Endothelial dysfunction, vascular inflammation, and VSMC remodeling underlie arteriosclerosis and atherosclerosis, which are accelerated in T2DM by hyperglycaemia, oxidative stress, dyslipidaemia, and chronic inflammation. Metabolic stress reprograms vascular cells, promoting oxidative damage, cytokine release, and vascular senescence, ultimately contributing to arterial stiffening, plaque instability, and intimal calcification. Understanding these immunometabolic interactions is critical for developing targeted therapies. Methods: We reviewed experimental, translational, and clinical studies, along with systematic and narrative reviews, to examine how metabolic and immune dysregulation drives vascular pathology. Results: Vascular inflammation and immunometabolic dysregulation are central drivers of CVD in T2DM. Immune–metabolic crosstalk, mechanical stress, and epigenetic regulation disrupt vascular homeostasis, causing endothelial dysfunction, VSMC phenotypic switching, extracellular matrix remodelling, arterial stiffening, and atherogenesis. Key factors—cytokine/chemokine signalling (IL-1β, IL-6, TNF-α), vasoactive hormones, metabolic blood components, mechanical stress, and epigenetic dysregulation—converge on pathways including oxidative stress, NF- κB and PI3K/AKT signalling, HIF-1α activation, AGE–RAGE interactions, inflammasome activation, and foam cell formation. Crosstalk among endothelial cells, macrophages, VSMCs, and adaptive immune cells drives plaque progression and vascular remodelling. Emerging mechanisms such as trained immunity and clonal haematopoiesis reveal persistent vascular inflammation and novel therapeutic targets. Pharmacological interventions—including GLP-1 receptor agonists, SGLT2 inhibitors, statins, RAAS blockers, and IL-1β inhibitors—alongside lifestyle measures, confer vascular protection beyond glycaemic control. Discussion: Immunometabolic dysregulation promotes persistent vascular inflammation, arterial stiffening, VSMC remodelling, and plaque progression. Mechanisms, including trained immunity and clonal haematopoiesis, contribute to residual cardiovascular risk, highlighting the need for integrated strategies targeting both metabolic and inflammatory pathways. Conclusion: Vascular dysfunction in T2DM arises from metabolic stress, immune activation, and vascular cell reprogramming. Trained immunity and clonal haematopoiesis provide insight into persistent vascular inflammation and residual cardiovascular risk. Combined pharmacological and lifestyle interventions, guided by integrative omics, offer precision strategies to reduce CVD risk. Future research should address cell-specific mechanisms, regulation of immune memory, and long-term outcomes to optimize cardiometabolic care.