Mechanisms in Atherogenesis and Vascular Remodeling: Targeting Disease Drivers

Atherogenesis and vascular remodeling are highly organized biological processes that unfold in spatially and temporally ways within the arterial wall. Rather than occurring uniformly, these changes emerge at specific vascular regions, such as arterial bifurcations and curved segments, where local cues shape cellular behavior. Understanding the cellular and subcellular mechanisms, including membrane trafficking and organelle dynamics, that guide atherogenesis and vascular remodeling is critical for identifying the key drivers of disease progression and for developing more precise therapeutic strategies.Endothelial cells are the first responders to biomechanical and biochemical signals within the vasculature. Variations in blood flow and shear stress create distinct endothelial phenotypes that determine susceptibility to atherosclerotic lesion formation. In regions of disturbed flow, endothelial cells exhibit altered vesicular trafficking, endocytosis, and exocytosis, leading to changes in membrane receptor distribution, barrier function, and proinflammatory signaling. These spatially defined subcellular responses act as early cues that initiate atherogenesis by promoting localized lipid retention and immune cell recruitment.Lipid accumulation and lipoprotein handling further reinforce spatial patterning during disease initiation and progression. Low-density lipoproteins preferentially deposit in regions of endothelial dysfunction, where altered vesicular transport and endosomal sorting facilitate lipid uptake, retention, and intracellular processing. Modified lipoproteins trigger localized inflammatory responses and promote foam cell formation, reinforcing heterogeneity within developing plaques. Organelle dynamics, including lysosomal function, lipid droplet formation, and endoplasmic reticulum (ER) stress, play critical roles in regulating cellular metabolism, calcium signaling, and inflammatory activation, thereby shaping plaque architecture and influencing vascular remodeling outcomes.As lesions develop, interactions among endothelial cells, smooth muscle cells, macrophages, and fibroblast-like cells become increasingly organized. Smooth muscle cells undergo phenotypic transitions coordinated with cytoskeletal remodeling and organelle redistribution, guided by local microenvironmental signals such as extracellular matrix composition, growth factors, and metabolic stress. These patterned transitions contribute to plaque growth, fibrous cap formation, and vessel wall thickening. Immune cells further reinforce spatial organization by targeted vesicular secretion, receptor trafficking, and organelle-mediated signaling, clustering within defined plaque regions to regulate inflammation, tissue remodeling, and plaque stability.Vascular remodeling extends beyond plaque formation and reflects adaptive and maladaptive responses to chronic injury. Structural changes in vessel architecture, including lumen narrowing, wall stiffening, and neovascularization, are regulated by intracellular trafficking networks, organelle crosstalk, and membrane dynamics, which often mirror developmental patterning programs.Targeting the drivers of these subcellularly patterned processes offers new opportunities for therapeutic intervention. Such approaches will accelerate the identification of disease drivers and support the development of precision therapies that restore healthy vascular structure and function.Key research areas include but are not limited to:• Spatial regulation of endothelial membrane trafficking and vesicular dynamics in atheroprone regions• Patterned smooth muscle cell phenotypic transitions coordinated with organelle redistribution• Lipoprotein handling, endosomal sorting, and channel protein regulation in plaque microenvironments• Organelle-mediated immune cell signaling and spatial organization during vascular remodeling• Therapeutic targeting of region-specific, subcellular disease drivers in the vasculature Topic editors: Vahitha Abdul Salam, Laura Bindila Source: https://www.frontiersin.org/research-topics/76961/mechanisms-in-atherogenesis-and-vascular-remodeling-targeting-disease-drivers