Atherosclerosis remains a leading cause of cardiovascular morbidity and mortality worldwide. Traditionally, clinicians viewed plaque formation primarily as passive lipid accumulation within arterial walls. However, contemporary research reveals that vascular immunometabolism coordinates chronic arterial inflammation and structural remodeling. During atherogenesis, immune and vascular cells shift their bioenergetics toward accelerated glucose utilization. This metabolic rewiring alters cellular function, fuels oxidative stress, and impairs plaque stability. Consequently, deciphering these metabolic circuits offers promising opportunities for targeted cardiovascular therapeutics.

Vascular Immunometabolism and Glycolytic Shifts in Macrophages

Macrophages serve as central orchestrators of plaque inflammation and lesion destabilization. Within the atherogenic microenvironment, pro-inflammatory macrophages undergo extensive glycometabolic reprogramming. Specifically, these immune cells upregulate glucose transporter 1 to accelerate intracellular glucose uptake. Furthermore, they enhance glycolytic flux to rapidly generate adenosine triphosphate for cytokine production. This metabolic shift closely mirrors the Warburg effect observed in oncology. In addition, macrophages reroute substantial glucose flux through the pentose phosphate pathway. This pathway generates abundant nicotinamide adenine dinucleotide phosphate, which fuels reactive oxygen species generation via NADPH oxidase. Consequently, heightened oxidative stress accelerates oxidized low-density lipoprotein uptake and foam cell formation. Moreover, disrupted mitochondrial oxidative phosphorylation impairs apoptotic cell clearance, known as efferocytosis. Thus, persistent glycolytic hyperactivity in plaque macrophages maintains non-resolving arterial inflammation and expands the necrotic core. Therefore, modulating macrophage vascular immunometabolism represents an attractive strategy to stabilize vulnerable plaques without inducing generalized immunosuppression.

Endothelial Glycometabolic Reprogramming and Angiogenesis

Endothelial cells line the arterial lumen and maintain vascular homeostasis under physiological laminar flow. However, disturbed hemodynamic shear stress and systemic dyslipidemia alter endothelial energy metabolism. Although endothelial cells contact oxygenated blood directly, they rely predominantly on anaerobic glycolysis for energy. In early atherosclerosis, excessive glycolytic activation compromises endothelial barrier integrity. Specifically, elevated expression of key glycolytic enzymes increases endothelial permeability, facilitating subendothelial low-density lipoprotein infiltration. Furthermore, hyper-glycolytic endothelial cells transition into invasive tip cells and proliferative stalk cells. Consequently, this transformation promotes pathological intraplaque neovascularization. These newly formed microvessels remain structurally immature and prone to leakage. Therefore, microvascular extravasation delivers erythrocytes and inflammatory cells directly into the deep lesion core. In addition, subsequent intraplaque hemorrhage markedly increases the risk of acute cardiovascular events. Thus, targeting endothelial bioenergetics offers a complementary path to improve vascular wall resilience against atherogenic insults.

Vascular Smooth Muscle Cell Phenotypic Switching

Vascular smooth muscle cells preserve the structural integrity of the arterial media under healthy conditions. However, local inflammatory stimuli and atherogenic lipids trigger a profound phenotypic switch. During this phenotypic transition, vascular smooth muscle cells abandon their contractile state and adopt synthetic, proliferative phenotypes. Importantly, this dedifferentiation relies on a dramatic metabolic shift toward aerobic glycolysis. Specifically, synthetic smooth muscle cells upregulate glucose transporters and glycolytic machinery to satisfy bioenergetic demands. Furthermore, enhanced glycolytic flux supports extensive cellular proliferation and migration into the subendothelial space. While synthetic cells initially construct a protective fibrous cap, excessive metabolic stress alters their fate. Consequently, prolonged glycometabolic reprogramming induces smooth muscle cell transdifferentiation into macrophage-like and osteogenic phenotypes. These transdifferentiated cells display impaired phagocytic capacity and accelerate vascular calcification. Therefore, restraining abnormal glycolytic reprogramming in smooth muscle cells represents a promising therapeutic avenue to preserve arterial elasticity and stability.

Lactate Signaling, Trained Immunity, and Epigenetic Remodeling

High glycolytic activity generates large quantities of lactate within the hypoxic atherosclerotic microenvironment. Historically viewed as a mere metabolic waste product, lactate now emerges as an active signaling molecule. Specifically, intracellular lactate accumulation fuels histone lactylation, a newly identified post-translational epigenetic modification. For example, recent investigations identify the TRAP1, HDAC3, and histone H4 lysine 12 lactylation axis as a critical regulatory mechanism in vascular lesions. Furthermore, lactate-mediated epigenetic remodeling sustains long-term pro-inflammatory memory in myeloid precursors, a process termed trained immunity. Because of trained immunity, circulating monocytes maintain a hyper-inflammatory state even after systemic lipid lowering. Consequently, transient metabolic insults like hypercholesterolemia imprint persistent chromatin alterations that accelerate atherogenesis. Moreover, chronic lactate accumulation acidifies the local microenvironment, which accelerates cellular senescence across vascular cells. Thus, uncoupling lactate generation from downstream chromatin machinery offers an innovative way to suppress trained immunity and stabilize chronic arterial lesions.

Therapeutic Targets and Clinical Translation Challenges

Delineating the vascular immunometabolic landscape uncovers several compelling therapeutic targets for atherosclerosis prevention and treatment. In particular, pharmacological inhibition of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 limits excessive glycolytic flux in endothelial cells and macrophages. Preclinical investigations demonstrate that small-molecule inhibitors of this enzyme diminish vascular inflammation and restrain intraplaque neovascularization. Similarly, targeting lactate dehydrogenase A prevents excess lactate accumulation and blocks downstream histone lactylation pathways. In addition, modulating mitochondrial chaperones such as tumor necrosis factor receptor-associated protein 1 provides another avenue to restore cellular metabolic equilibrium. However, translating these experimental discoveries into routine clinical practice presents notable pharmacological challenges. Because glycolysis supplies essential baseline energy to non-diseased organs, systemic glycolytic blockade poses toxic risks to the myocardium and erythrocytes. Therefore, researchers must engineer cell-selective delivery platforms, including antibody-conjugated nanoparticles and lesion-specific nanocarriers. Ultimately, overcoming these translational hurdles will allow targeted immunometabolic therapies to neutralize residual cardiovascular risk.

How does glycometabolic reprogramming influence macrophage polarization in plaques?

Glycometabolic reprogramming actively dictates macrophage polarization within atherosclerotic plaques. Exposure to inflammatory cytokines and oxidized lipids upregulates glucose transporter 1 and key glycolytic enzymes. Consequently, macrophages shift energy production toward aerobic glycolysis and the pentose phosphate pathway. This bioenergetic rewiring accelerates reactive oxygen species production and interleukin secretion, locking macrophages into a persistent pro-inflammatory state. In contrast, oxidative phosphorylation supports anti-inflammatory tissue repair, which remains suppressed in progressive lesions.

What role does histone lactylation play in vascular immunometabolic memory?

Histone lactylation links cellular glycometabolism directly to epigenetic gene transcription. When vascular cells and macrophages undergo sustained glycolysis, accumulated lactate acts as a functional substrate for histone lysine modification. Specifically, histone H4 lysine 12 lactylation alters chromatin accessibility, perpetuating the transcription of pro-inflammatory and pro-fibrotic genes. This epigenetic modification sustains trained immunity in myeloid cells, meaning vascular inflammation persists even after systemic lipid levels normalize following statin or lifestyle interventions.

Why is systemic inhibition of glycolysis problematic in clinical cardiovascular care?

Systemic inhibition of glycolysis carries substantial clinical toxicity because most healthy tissues depend on glucose for fundamental survival. For instance, erythrocytes lack mitochondria and rely exclusively on glycolysis for adenosine triphosphate generation. Furthermore, the brain and myocardium require continuous glucose flux during physiological stress. Consequently, non-selective systemic glycolytic inhibitors cause severe adverse reactions, including hemolytic anemia and metabolic fatigue. Researchers must therefore develop targeted delivery vehicles that restrict drug action specifically to inflamed arterial plaques.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice, diagnosis, or treatment. Healthcare professionals should exercise their independent clinical judgment when evaluating medical literature. Refer to the latest local and national guidelines for clinical practice.

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