Pathophysiological basis of atherosclerosis: endothelial inflammation and hyperlipidemia

It is well known that atherosclerosis is a chronic, progressive disease of the arterial wall, characterized by lipid accumulation, oxidative stress, and immune system activation, leading to plaque formation and vascular obstruction. The initiating event in this process is endothelial dysfunction - a loss of the endothelium’s ability to maintain vascular homeostasis and regulate the balance between vasodilation, coagulation, and inflammation.7

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Under physiological conditions, endothelial cells produce nitric oxide (NO), prostacyclin, and other mediators that inhibit leukocyte adhesion and smooth muscle proliferation. When exposed to risk factors such as hyperlipidemia, hypertension, diabetes, and smoking, the endothelium becomes activated, expressing adhesion molecules like VCAM-1 and ICAM-1, which recruit monocytes into the intima.7,8

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Monocytes differentiate into macrophages, internalize oxidized LDL (oxLDL), and transform into foam cells, generating pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which further amplify local inflammation. This cycle of endothelial activation, leukocyte recruitment, and cytokine release maintains a chronic inflammatory milieu that promotes smooth muscle cell migration and extracellular matrix remodeling, leading to the development of fibrous plaques. The instability of these plaques—characterized by a thin fibrous cap and a large lipid core—is responsible for most acute coronary syndromes through plaque rupture and thrombosis.9,10

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While current therapies like statins and antiplatelet agents reduce systemic inflammation and lipid levels, they do not reverse endothelial injury or restore vascular integrity. This limitation has stimulated interest in regenerative and cellular mechanisms—particularly those mediated by extracellular vesicles—that could induce true vascular healing rather than mere disease stabilisation.11

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Exosome biology: biogenesis and functional relevance in vascular systems

Exosomes are nanosized (30–150 nm) extracellular vesicles of endosomal origin released by nearly all cell types, including endothelial cells, smooth muscle cells, platelets, and macrophages. They are generated through the inward budding of multivesicular bodies (MVBs) and subsequently secreted upon fusion of MVBs with the plasma membrane.12 Exosomes contain a complex cargo of bioactive molecules, including microRNAs (miRNAs), messenger RNAs, proteins, lipids, and signaling molecules that reflect the physiological or pathological state of their parent cells.4

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According to findings, endothelial-derived exosomes play a crucial role in maintaining vascular tone, angiogenesis, and intercellular signaling. They mediate communication between endothelial cells, smooth muscle cells, and immune cells, thereby influencing vascular remodeling and inflammatory responses. For example, exosomes enriched in miR-126 and miR-21 play prominent roles in enhancing endothelial proliferation, migration, and angiogenic capacity. They enhance endothelial repair, promote NO production via the PI3K/Akt/eNOS pathway, and suppress NF-κB–mediated inflammation. Similarly, mesenchymal stem cell (MSC)-derived exosomes exert anti-inflammatory and anti-apoptotic effects on endothelial cells, reducing oxidative stress and improving angiogenesis.13-15

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The uptake of exosomes by recipient cells occurs through multiple mechanisms - endocytosis, micropinocytosis, and receptor-mediated fusion - facilitated by surface molecules such as tetraspanins (CD9, CD63, CD81) and integrins that determine target-cell specificity. Once internalized, exosomal cargo can reprogram gene expression in target cells, effectively restoring endothelial homeostasis and function.

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Because of these properties, exosomes have emerged as natural nanocarriers capable of delivering regenerative signals in cardiovascular diseases. Their ability to traverse biological barriers, low immunogenicity, and intrinsic targeting capacity make them promising tools for vascular repair and as prototypes for the development of biological stent platforms that combine mechanical support with molecular regeneration.16

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Exosome-mediated endothelial repair: anti-inflammatory effects of exosomal cargo

Endothelial repair is a critical determinant of vascular homeostasis, particularly during atherosclerotic plaque development and progression. Exosomes derived from endothelial cells, mesenchymal stem cells, and cardiac progenitor cells have been increasingly recognized as key mediators of vascular regeneration by delivering bioactive cargo to dysfunctional endothelial cells.

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Beyond cellular repair, exosomes contribute to plaque stabilization by modulating the balance between lipid accumulation and extracellular matrix formation. Studies in ApoE⁻/⁻ mice have demonstrated that the administration of MSC-derived exosomes leads to reduced aortic plaque burden, increased fibrous cap thickness, and decreased necrotic core size.17 These effects were partly attributed to reduced macrophage infiltration and enhanced collagen deposition, suggesting that exosomes facilitate the transition from an unstable, rupture-prone plaque towards a more stable phenotype. Furthermore, exosomes enriched in miR-143/145 clusters have been shown to regulate smooth muscle cell phenotypic switching, promoting a contractile rather than a synthetic phenotype and thereby contributing to plaque stabilization.18,19

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In vitro scratch-wound and tube formation assays have consistently confirmed the pro-reparative effects of exosomes on endothelial cell monolayers, demonstrating accelerated wound closure, enhanced vascular network formation, and improved endothelial barrier integrity following exosome exposure.20 In addition, exosomal cargo has been reported to attenuate endothelial-to-mesenchymal transition (EndMT), a key process in plaque progression that results in loss of endothelial identity and acquisition of a pro-fibrotic, pro-inflammatory phenotype.21 By preserving endothelial lineage markers such as CD31 and VE-cadherin, exosomes help maintain vascular stability and reduce plaque vulnerability.

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Taken together, exosomes exert a dual regenerative effect in atherosclerosis by promoting endothelial repair and plaque stabilization. Their ability to activate angiogenic pathways, enhance NO production, restore endothelial barrier function, and modulate extracellular matrix remodeling positions them as promising therapeutic agents in reversing vascular injury. These findings form a critical foundation for exploring exosome-based vascular regeneration strategies and support the development of future therapeutic strategies.

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As mentioned before, exosomes have emerged as key modulators of inflammatory signaling pathways through their cargo of regulatory microRNAs, proteins, and lipids that suppress immune activation and promote plaque stabilization.

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One of the most extensively studied exosome-derived microRNAs is miR-21, which reduces inflammation by inhibiting the PTEN/NF-κB pathway, thereby downregulating pro-inflammatory gene expression and reducing macrophage activation.22

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Mesenchymal stem cell-derived exosomes have also been shown to shift macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, thereby enhancing tissue healing and reducing lesion progression.23

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Similarly, exosomes containing miR-146a suppress toll-like receptor signaling and downstream NF-κB activation, attenuating endothelial and macrophage-mediated inflammatory responses.24

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In animal models of atherosclerosis, treatment with exosomes carrying anti-inflammatory miRNAs resulted in decreased levels of circulating IL-1β, IL-6, and C-reactive protein, suggesting systemic immunomodulation.25

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In addition to inflammatory control, exosomes contribute to lipid homeostasis and foam cell regulation, which are essential for reducing plaque lipid burden. For example, exosomes enriched in miR-33 and miR-758 have been reported to modulate cholesterol efflux by regulating ATP-binding cassette transporters ABCA1 and ABCG1, thereby reducing foam cell formation.

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Moreover, endothelial-derived exosomes carrying miR-126 help maintain vascular integrity and prevent leukocyte adhesion, indirectly reducing lipid deposition and inflammatory infiltration.

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In summary, exosome-based therapy holds promise as a therapeutic strategy that extends beyond traditional pharmacologic interventions focused solely on systemic lipid lowering or symptom control.