Predisposing factors for stress-induced vascular senescence

Blood vessels are composed of the intima, media, and adventitia, and the main cell types include VECs, VSMCs, and fibroblasts. Damage to any vessel layer or cell type can contribute to stress-induced vascular senescence [10]. VECs form a single layer of flat squamous epithelial cells lining the inner wall of blood vessels, serving as a protective barrier for material exchange between blood and tissues. They regulate biological processes such as oxidative stress, inflammation, vasomotor function, and coagulation by maintaining the integrity of the vascular system, and they are an important link in preserving vascular and internal environmental homeostasis [11]. VEC dysfunction, which has been extensively studied, is a pathological basis closely related to stress-induced vascular senescence that can cause blood flow disorders [12], impair vascular repair and regeneration, reduce the permeability of vascular endothelial cells, and damage the integrity of the cardiovascular system by affecting oxidative stress, inflammatory responses, autophagy, and other functions [13]. The main inducible factors of stress-induced vascular senescence are summarized in Figure 1.

Figure 1:: Factors contributing to stress-induced vascular senescence.

OS

OS is a pathological condition in which the overproduction and impaired elimination of ROS can damage cellular DNA and proteins, destroy the cell membrane and membranous organelles, and induce cellular aging or even death, forming the pathological basis for atherosclerosis, heart failure, arterial hypertension, and other CVDs [4], [14], [15], [16]. As an important second messenger in the body, ROS participate in the transduction of intracellular signals in various biological processes. Its excessive accumulation, triggered by exogenous factors such as radiation, certain drugs, high-sugar foods, and tobacco or endogenous factors such as mitochondrial dysfunction and autophagy disorders can trigger OS, directly damage cellular DNA and proteins, and induce VEC dysfunction [14], [15], [16]. Moreover, if the body exhibits abnormalities in scavenging enzyme systems such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), ROS cannot be cleared normally, resulting in their abnormal accumulation [17].

Accumulated ROS can modify the molecular structure of cellular DNA, proteins, and lipids, disrupt the phospholipid bilayer, and cause damage to cell membranes, membranous organelles, and genomes, resulting in tissue and organ damage [18]. Abnormal ROS levels can also alter the activation state of endothelial nitric oxide synthase (eNOS), reduce the production and bioavailability of NO, impair the body’s ability to regulate vasomotion, inflammation, and thrombosis, and promote the formation of the atherosclerotic vascular phenotype during aging, which is an important mechanism driving cellular aging [19]. OS can also cause telomere shortening, resulting in genomic instability and leading to cell apoptosis and necrosis [20]. OS activates redox-sensitive cell signaling pathways, induces the expression of numerous pro-inflammatory factors and mediators, inhibits the expression of anti-inflammatory factors, and aggravates stress-induced vascular senescence secondary to inflammatory injury [21]. VEC dysfunction caused by OS affects coronary artery dilation and induces neurovascular uncoupling, which may contribute to the development of heart and brain diseases [22]. The generation of ROS is the basis of persistent oxidative stress and is involved in the pathogenesis of many CVDs. OS-induced, stress-induced vascular senescence involves multiple pathways and channels. Endothelial cells in the intima, VSMCs in the media, and macrophages in the adventitia can generate superoxide anion radicals through different pathways, thus promoting vascular oxidative stress responses [13], 23]. Most of the above-mentioned conclusions are supported by abundant in vitro and animal experimental evidence, while direct clinical data on human vascular aging are still lacking.

Inflammation

Inflammation is the physiological response of organisms to harmful stimuli. By triggering the production of numerous inflammatory factors, such as chemokines, cyclooxygenase-2, cytokines, and pro-inflammatory transcription factors, the invasion of harmful stimuli can be mitigated, but a persistent inflammatory response can lead to cell and tissue damage [24]. When the body is exposed to harmful stimuli, the expression of pro-inflammatory genes associated with vascular endothelial cells and smooth muscle cells is upregulated, and large numbers of white blood cells are mobilized to infiltrate the vascular wall, creating a pro-inflammatory microenvironment that can readily cause apoptosis of vascular wall cells and induce vascular dysfunction [25]. Inflammatory factors produced during inflammation can exhaust the adaptive immune response, leading to immune aging, which may combine with the inflammatory response to create a vicious cycle that ultimately worsens tissue damage. Many factors, such as DNA damage, organelle dysfunction, autophagy defects, and stem cell aging, can promote inflammation, which is closely associated with oxidative stress [26]. Excess ROS regulate the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and other inflammatory molecules, leading to secondary inflammatory responses and inflammatory damage [27].

Beyond local vascular cytokines detected in tissue specimens, the concept of inflammaging emphasizes a systemic, chronic, low-grade inflammatory state as a key driver of stress-induced vascular senescence, with measurable circulating inflammatory biomarkers serving as translational surrogates for assessing the severity of stress-induced vascular senescence and cardiovascular prognosis [28]. Unlike individual inflammatory cytokines such as IL-6 and TNF-α, composite systemic immune-inflammatory indices derived from routine blood cell counts (including the systemic immune-inflammation index (SII), CRP/albumin ratio (CAR), and uric acid/albumin ratio (UAR)) allow standardized quantitative stratification of the overall inflammatory burden. Longitudinal cohort analyses have confirmed that elevated composite inflammatory markers are independently associated with increased arterial stiffness and carotid intima-media thickness, two classic non-invasive indicators of premature stress-induced vascular senescence [29]. Sustained systemic inflammation accelerates secretion of the endothelial senescence-associated secretory phenotype (SASP), intensifies vascular wall remodeling, and creates a feedforward cycle between inflammatory burden and progressive premature stress-induced vascular senescence [4].

Two clinical studies explicitly confirmed the prognostic value of composite inflammatory indices, as suggested by the peer review comments. First, elevated SII serves as an independent predictive marker for contrast-induced nephropathy in patients with non-ST-segment elevation myocardial infarction; microvascular senescence and endothelial injury caused by systemic inflammatory activation underlie this adverse renal complication following coronary angiography [30]. Second, direct comparisons of multiple inflammatory indices for determining atrial fibrillation recurrence after cryo-ablation show that CAR has better predictive performance than SII and UAR; persistent systemic inflammation promotes chronic atrial stress-induced vascular senescence and structural remodeling, increasing the risk of arrhythmia recurrence in patients with high composite inflammatory index tertiles [31]. Taken together, these clinical observations connect preclinical mechanistic research on inflammation-driven stress-induced vascular senescence with clinical risk stratification, offering measurable laboratory indicators that help translate basic stress-induced vascular senescence mechanisms into practical tools for cardiovascular risk assessment [4], 27].

Autophagy

Autophagy can regenerate metabolic precursors, remove subcellular debris, enhance the quality of organelles and proteins, and maintain cellular homeostasis and integrity under stress. Impairments in autophagy can accelerate the onset and progression of pathological biological processes such as oxidative stress, inflammatory responses, and cell necrosis [32], 33]. Autophagic capacity can decline with age, and a reduced rate of autophagic clearance of poor-quality proteins leads to the continuous accumulation of toxic aggregates in cells, contributing to cellular necrosis and triggering tissue injury [34], 35]. The accumulation of ROS, cytokines, and growth factors in vascular smooth muscle cells can activate autophagy and mitigate damage to these cells [36]. Mitophagy can protect VECs under stress (e.g., hypoxia) by removing damaged mitochondria and reducing the intracellular accumulation of harmful substances such as ROS, thus alleviating VEC injury [37]. However, excessive autophagy can destroy essential organelles and proteins, leading to autophagy-associated cell death and promoting VEC dysfunction [38]. Studies have shown that administering an autophagy enhancer to elderly mice can reduce oxidative stress and inflammation and may even reverse age-related vascular dysfunction [39].

Telomeres and telomerase

Telomeres are complex structures composed of DNA and proteins located at the ends of normal chromosomes. They play an important role in reducing DNA degradation, recombination, and fusion, and they shorten as the number of cell divisions increases [40], 41]. When telomeres shorten to a certain extent, chromosome ends become exposed, triggering a cascade signal similar to DNA damage, which induces inflammatory gene expression and a senescence-associated secretory phenotype [41]. The senescence-associated secretory phenotype of paracrine factors has been shown to induce senescence in neighboring cells [42]. Telomere shortening can be accelerated by senescence, oxidative stress, and inflammatory responses. When telomeres become critically short, the resulting genomic instability activates the DNA repair system and induces cellular replication arrest, senescence, and cell death. In senescent cells, the secretion of pro-inflammatory cytokines, adhesion molecules, growth factors, and other inflammatory mediators is significantly increased, which further worsens telomere dysfunction, promotes replicative aging, creates a vicious cycle, and accelerates the progression of senescence and age-related diseases [43].

Mitochondrial function

Mitochondrial function is impaired by a variety of factors, including the accumulation of mitochondrial DNA mutations, imbalances in the respiratory chain complex, and changes in mitochondrial dynamics, which increase ROS production and trigger alterations in mitochondrial membrane permeability, leading to oxidative stress, inflammation, apoptosis, and stress-induced vascular senescence [44]. ROS attacks on mitochondria lead to increased mitochondrial DNA damage, reduced levels of respiratory chain-related enzymes synthesized by mitochondrial DNA, and a decreased ability of the body to repair the damage, resulting in cell dysfunction [45]. The iron-sulfur center of the electron transport chain in eukaryotic cells can be oxidized by mitochondrial ROS, causing functional damage to the ETC complex and further increasing ROS production [46]. Mitochondrial dysfunction may affect IL-6 signaling through a positive feedback loop, thus influencing inflammatory responses and exacerbating stress-induced vascular senescence [47].

NO

NO, as an endothelium-derived relaxing factor, can dilate blood vessels, scavenge oxygen free radicals, inhibit platelet adhesion, reduce adhesion of inflammatory factors, provide antioxidant, anti-inflammatory, antithrombotic, and blood flow-regulating effects, and mitigate stress-induced vascular senescence. NO stimulates telomerase activity, counteracts the adverse effects of telomere shortening, reduces NO donor erosion, and relieves oxidative stress-induced VEC senescence [48]. VEC dysfunction causes ROS accumulation, which lowers intracellular l-arginine levels and impairs the cofactor activity of eNOS, leading to decreased NO production, disruption of the intravascular environment, and worsening of VEC injury [49].

RAAS

The hyperactivity of RAAS induces OS and chronic inflammatory responses, increases the incidence of vascular atherosclerosis, makes vascular cells more vulnerable to damage, and promotes stress-induced vascular senescence [50]. Angiotensin II expression and activation mediate intimal fiborsis, resulting in the deposition of collagen and fibronectin and the degradation of elastin, which cause structural changes in the vasculature and lead to stress-induced vascular senescence [51]. Abnormal activation of the salt corticosteroid receptor by aldosterone can induce changes in the vascular structure and function through various mechanisms, including effects on oxidative stress, inflammatory responses, and vascular tone [52]. Studies have shown that inhibiting RAAS activity can reduce arterial stiffness in olde r adults and aged animals, regulate changes in blood pressure, and improve the ability of blood vessels to resist aging [53].