Air Pollution and Stroke: An Emerging Challenge From Cardio‐Cerebrovascular Multimorbidity

Abstract

Cerebrovascular disease, as represented by stroke, was identified as one of the leading causes of death worldwide. Although air pollution was widely documented to be associated with stroke, the underlying mechanism of such adverse effects remained largely unknown. Cardiovascular effects triggered by air pollution were regarded as the dominant contributor to stroke pathogenesis, indicating the interconnected pathological basis of cardio‐cerebrovascular multimorbidity in driving acute cerebrovascular events. By adopting the adverse outcome pathway as a pivotal tool, this review summarized air pollution–related effects on the cerebral blood flow into 3 aspects, namely, direct damage to the cerebrovascular system, systemic inflammation from the pulmonary to the cardiovascular system, and blood pressure changes mediated by the autonomic nervous system. After triggering molecular initiating events such as reactive oxygen species generation and sensory receptor activation, air pollutants may cause key events affecting the blood–brain barrier integrity, thrombosis, atherosclerosis, and hypertension, eventually leading to acute cerebrovascular events. This review underscored the critical role of cardio‐cerebrovascular multimorbidity in air pollution–related cerebrovascular disease, suggesting a complex interplay of mechanisms affecting brain health. Even at a relatively low exposure level, air pollution remained a latent but modifiable risk factor for stroke, emphasizing the urgent need for interventions to mitigate this public health threat and timely risk factor management for high‐risk individuals.

Nonstandard Abbreviations and Acronyms

AOP

adverse outcome pathway

AQG

Air Quality Guidelines

BBB

blood–brain barrier

China‐PAR

Prediction for ASCVD Risk in China

ELAPSE

Effects of Low‐Level Air Pollution: A Study in Europe

GBD

Global Burden of Disease Study

KE

key event

MCAO

middle cerebral artery occlusion

PM

particulate matter

ROS

reactive oxygen species

TRP

transient receptor potential

WHO

World Health Organization

Air pollution, especially ambient particulate matter (PM) pollution, was the leading cause of global disease burden in 2021, accounting for 8.0% of total disability‐adjusted life years. ¹ After the update of annual limits for major air pollutants in World Health Organization (WHO) Air Quality Guidelines (AQG), a recent report indicated that >94% of the world's population still exposed to fine particulate matter (PM_2.5) higher than the AQG limit (5 μg/m³), suggesting a persistent health threat in the future. ² According to the latest findings from the GBD (Global Burden of Disease) study 2021, acute cardiovascular events including ischemic heart disease and stroke were among the major causes of air pollution–related global death, accounting for 28% and 27% of deaths, respectively. ³ Despite constant efforts in improving air quality, recent studies reported that air pollutants such as PM_2.5 could still increase risks of cardiovascular diseases even at a relatively low exposure levels (<15 μg/m³). ⁴ While much has been learned from recent studies, there are still gaps in understanding the full complexity of the underlying mechanisms due to variability in experimental models and methodologies. ⁵

Air pollution was extensively documented to trigger pathological changes including atherosclerosis, thrombosis, and hypertension, which were also regarded as essential contributors to stroke pathogenesis. ⁶ Indeed, air pollution was found to be involved in almost every transition stage for the development of cardio‐cerebrovascular multimorbidity, and these shared mechanisms may coordinate to spark an acute cerebrovascular event. Cerebrovascular disease was the primary cause of death and disability among both neurological and cardiovascular diseases, with stroke ranked the third global leading cause of deaths in 2021. ⁷ Although treatment and rehabilitation approaches have been established for the acute onset of stroke, stroke prevention remains the predominant strategy in reducing death and disability in the general population. ⁸ Therefore, it is valuable to set up a complete theoretical framework to integrate the interconnected impact of air pollution on the cardiovascular and cerebrovascular systems, thus elucidating the mechanisms linking air pollution to the occurrence and progression of strokes.

To the very best of our knowledge, this review is the first to adopt the adverse outcome pathway (AOP) as a pivotal tool to establish a comprehensive panorama of air pollution–related cerebrovascular disease from initiating changes at the molecular or cellular level to the occurrence of clinical syndrome. According to the guidance of the Organization for Economic Cooperation and Development's AOP development handbook, ⁹ we identified the molecular initiating event, key event (KE), and adverse outcome based on content from the AOP wiki and results from both epidemiological and toxicological studies. Considering existing theory of air pollution–related cardiovascular effects and the latest findings of their impact on the cerebral vasculature, the underlying mechanisms for cerebrovascular disease were built at 3 aspects (Figure 1). ¹⁰ The first section suggested that air pollutants like PM at the nanoscale could directly enter the central nervous system (CNS), impairing the blood–brain barrier (BBB) integrity by triggering the inflammatory signaling cascades in endothelial cells and microglia. The second section considered that air pollutants could induce systemic inflammation from the pulmonary to the cardiovascular system, eventually leading to thrombosis and atherosclerosis. The last section speculated that air pollutants activated sensory receptors and enhanced the activity of the sympathetic nervous system, which altered the hemodynamics and resulted in hypertension. All 3 mechanistic pathways could act together to influence the integrity and perfusion of cerebral vasculature. Finally, this review will also comprehensively review all direct evidence about air pollution–induced cerebrovascular events to identify limitations of current knowledge, clarify the clinical implications, and further provide an expectation for future studies. The Bradford–Hill weight‐of‐evidence considerations is adopted to evaluate the relationship between KEs (Table 1), and details about this method have been discussed in our previous AOPs. ¹¹ , ¹² Considering the length limitations, we prioritize the inclusion of the most recent published literature and those with causality verification in this review. Current evidence suggests that both gaseous and particulate components of air pollution share analogous toxicological mechanisms, including induction of oxidative stress, systemic inflammatory responses, and endothelial dysfunction. ¹³ However, laboratory investigations into gaseous pollutants remain insufficient, particularly regarding challenges in replicating their real‐world exposure dynamics by in vitro models. Given these limitations, this review primarily focuses on PM while incorporating existing experimental and epidemiological evidence pertaining to gaseous pollutants.

Figure 1. AOP diagram of air pollution–related cerebrovascular disease.

The AOP Wiki (https://aopwiki.org) provided an identity number for each KE when they were first established, and they could be identified as either a molecular initiating event, KE, or an adverse outcome in different AOP frameworks. AO indicates adverse outcome; AOP, adverse outcome pathway; BBB, blood–brain barrier; KE, key event; and ROS, reactive oxygen species.

Table 1.

Summary and Evaluation of Key Event Relationships from the AOP

Upstream event	Relationship type	Downstream event	Weight of evidence
			Biological plausibility	Essentiality	Empirical evidence
ROS generation	Adjacent	Oxidative stress	Strong	Strong	Strong
ROS generation	Adjacent	Macrophage activation	Strong	Strong	Strong
Activating sensory receptors	Adjacent	Increased sympathetic activity	Strong	Strong	Strong
Oxidative stress	Adjacent	Inflammatory signaling pathways	Strong	Strong	Strong
Macrophage activation	Adjacent	Proinflammatory mediators	Strong	Strong	Strong
Inflammatory signaling pathways	Adjacent	Microglial activation	Strong	Strong	Strong
Proinflammatory mediators	Adjacent	Endothelial dysfunction	Strong	Moderate	Strong
Increased sympathetic activity	Adjacent	Increased stress hormone	Strong	Moderate	Strong
Microglial activation	Adjacent	Increased BBB permeability	Strong	Strong	Strong
Endothelial dysfunction	Adjacent	Atherosclerosis	Strong	Strong	Strong
Endothelial dysfunction	Adjacent	Thrombosis	Strong	Moderate	Strong
Increased stress hormone	Adjacent	Hypertension	Strong	Strong	Strong
Increased BBB permeability	Adjacent	Cerebrovascular disease	Strong	Moderate	Strong
Atherosclerosis	Adjacent	Cerebrovascular disease	Strong	Moderate	Strong
Thrombosis	Adjacent	Cerebrovascular disease	Strong	Moderate	Strong
Hypertension	Adjacent	Cerebrovascular disease	Strong	Moderate	Strong

AOP indicates adverse outcome pathway; BBB, blood–brain barrier; and ROS, reactive oxygen species.

Components of Air Pollution

Air pollution could be further classified as indoor and ambient pollution according to their sources. Although they are both established risk factors for stroke, ambient PM pollution ranks first among environmental risks for stroke, accounting for 16.6% of total stroke burden in 2021. ¹⁴ Since most existing laboratory studies mainly focused on ambient air pollution, this review focuses on discussing the cerebrovascular effects from ambient pollutants. Air pollution was a complex mixture consisting of solid, liquid, and gaseous pollutants, which could be derived from either natural or artificial sources. PM was the most predominant and well‐known contributor of air pollution, according to their aerodynamic diameter could be further divided into inhalable PM (PM₁₀, diameter <10 μm), fine PM (PM_2.5, diameter <2.5 μm), and ultrafine PM (PM_0.1, diameter <0.1 μm). PM_2.5 has received greater scientific attention due to its longer airborne suspension time and deeper lung penetration, with a significant proportion depositing in the alveoli rather than being cleared by upper airway defenses. ¹⁰ PM originates from both primary emissions (combustion processes, crustal dust, and mechanical abrasion) and secondary formation through atmospheric reactions of gaseous precursors. This dual origin results in complex mixtures containing organic compounds, heavy metals, and inorganic ions. ¹⁵ In 2021, the WHO revised the recommended AQG level for long‐term exposure to PM_2.5, which suggested an annual concentration limit for PM_2.5 at 5 μg/m³ to avoid the latent increase of nonaccidental death in long‐term exposure. However, after the establishment of the latest annual AQG level, a global exposure estimation conducted by the World Bank reported that 7.3 billion people (94% of the world's population) still lived with PM_2.5 considered unsafe (>5 μg/m³) by the WHO. The health threats imposed by PM_2.5 may be extremely severe in populations with low income, as the world's 2 largest developing countries, India and China had the largest proportion ([99%] for both) of residents facing unsafe PM_2.5 exposure. ²

Other major components of air pollution include SO₂, NO_x, O₃, carbon monoxide (CO), and volatile organic compounds. Gaseous pollutants including SO₂ and NO_x could be chemically transformed into their correlated inorganic ions such as ${\mathrm{SO}}_4^{2-}$ and ${\mathrm{NO}}_3^{-}$ after entering the body, resulting in transient irritation of the respiratory tract after short‐term exposure and systemic inflammation as a long‐term effect. O₃ is a naturally occurring atmospheric constituent that plays critical roles in atmospheric chemistry. With climate change and global warming, increasing attention has been focused on this highly reactive and oxidative compound due to growing evidence of its adverse cardiovascular effects. In the developed regions, ambient CO is frequently at a low level because of the adoption of emission controls like catalytic converters on cars; nonetheless, significant amounts can be found close to burning sources like wildfires. Volatile organic compounds such as methane, benzene, and polyaromatic hydrocarbons may exist in either liquid or gaseous form in the air and are also involved in the formation of O₃, PM, or other secondary aerosols. ¹⁰ , ¹⁵ Notably, air pollutants exert combined effects on the cardiovascular and cerebrovascular systems. Both gaseous and liquid constituents can adhere to PM, resulting in complex health effects in an additive manner. However, most of the existing studies could only evaluate the independent effects of several major pollutants, while it remained challenging to reveal the combined effects in the real world.

Direct Evidence Linking Air Pollution to Stroke

Epidemiological Studies

Numerous population‐based studies have reported the association between air pollution and acute cerebrovascular events, especially the hospitalization and death from stroke, which have been extensively reviewed in recent published literature. ⁵ , ¹⁶ A comprehensive meta‐analysis published in 2015 incorporated 94 studies from 28 countries, which concluded a weak but significant association between short‐term exposure to multiple air pollutants (PM₁₀, PM_2.5, CO, SO₂, NO₂, and O₃) to hospital admission or death from stroke. ¹⁷ The pooled relative risk was highest for PM_2.5 (1.011 per 10 μg/m³ [95% CI, 1.011–1.012]), while lowest for O₃ (1.001 per 10 ppb [95% CI, 1.000–1.002]), and the strongest association was observed on the exposure day (lag 0) for each pollutant. In a recently published multicenter study from China, where the residues still suffered a relatively higher air pollution than most developed countries, Lv et al reported that even hourly exposure to PM_2.5, PM₁₀, NO₂, and SO₂ were associated with elevated hospital admission rates for either total stroke or ischemic stroke, and these association were strongest during the first hour of exposure and lasted for almost 2 hours. ¹⁸

Accumulated evidence also demonstrated that long‐term exposure (from months to years) to air pollution, especially PM pollution, could be a risk factor in triggering acute cerebrovascular events. Scheers et al first conducted a meta‐analysis integrated 20 studies with >10 million subjects in 2015, and they recorded weak but significant pooled hazard ratios for long‐term PM (both PM_2.5 and PM₁₀) exposure and total stroke incidence (1.061 per 10 μg/m³ [95% CI, 1.018–1.105]), and more intriguingly, they observed that the association between PM₁₀ and stroke incidence was relatively stronger in studies from North America and Europe rather than Asia, where the air pollution level was generally considered to be lower. ¹⁹ These results were also confirmed by Alexeeff et al on the basis of 69 studies focusing on long‐term PM_2.5 exposure‐related cardiovascular events, they calculated a 13% increase of stroke incidence and a 24% elevation of cerebrovascular death induced by per 10 μg/m³ incremental exposure to PM_2.5. ²⁰ The China‐PAR (Prediction for ASCVD Risk in China) study conducted a long‐term observation for 15 years with >10 000 participants from 15 provinces across the country, which reported a significant and almost linear relationship between long‐term PM_2.5 exposure and all subtypes of stroke. Of note, PM_2.5 exposure in this study ranged from 31.2 to 97.0 μg/m³, and the results indicated that such a high level of PM_2.5 exposure increased a relatively higher risk for ischemic stroke (20% per 10 μg/m³) than hemorrhagic stroke (12% per 10 μg/m³). ²¹ In accordance with other findings, air pollution was not consistently associated with all subtypes of stroke, and most studies reported only a strong relationship between air pollution and ischemic but not hemorrhagic stroke. ¹⁶ , ²² This may be an explanation for several negative results found by studies adopting the overall stroke death or hospitalization as a single outcome without distinguishing subtypes. ²³

Considering the latest adjustment of the WHO AQG with specifically more tightened annual limitations for PM_2.5 and NO₂, this review emphasizes the findings from regions with general lower levels of air pollution. The ELAPSE (Effects of Low‐Level Air Pollution: A Study in Europe) study provided the latest and most reliable evidence on the basis of a 19.5‐year average follow‐up time with >32 000 participants from developed countries including Sweden, Denmark, Germany, and the Netherlands with a relatively low exposure load to air pollution, which reported that PM_2.5, NO₂, and black carbon were associated with all‐cause and cerebrovascular death. This study highlighted that even at an average exposure level below 25 μg/m³ (the EU limit level), per 5 μg/m³ increment of PM_2.5 exposure was associated with an 12.8% increase in cerebrovascular death. ²⁴ Another pooled analysis of the ELAPSE project indicated that PM_2.5 (<25 μg/m³) was significantly associated with elevated incidence (10% per 5 μg/m³) of stroke, while an even stronger increase (20% per 5 μg/m³) was found for PM_2.5 <15 μg/m³ (WHO level 3 interim level). Similar effects were also found for NO₂, with an 8% augment per 10 μg/m³ of stroke incidence when <40 μg/m³ (WHO level 1 interim level) but a 17% increment when <30 μg/m³. ²⁵ , ²⁶ These results primarily suggested that even at a relatively low concentration, air pollutants remained a potent threat to cerebrovascular health with a steeper dose–response curve.

Demographic characteristics (age, sex), socioeconomic status, and behavioral risk factors collectively modify the association between air pollution and stroke, resulting in differential population susceptibility to pollution‐mediated cerebrovascular effects. Age modifies the onset of cardiometabolic disease caused by air pollution, with long‐term exposure to PM_2.5 and NO₂ conferring a significantly higher risk in older populations (age >60 years) compared with younger individuals (<60 years). ²⁷ Women experience a disproportionate burden of stroke, exhibiting higher mortality rates and lifetime risk compared with men. Key modifiable risk factors, such as diabetes and hypertension, demonstrate a stronger association with stroke incidence in women. ²⁸ However, the role of sex in air pollution–related stroke remained unclear. Most studies reported that PM_2.5 and O₃ had a stronger association with stroke among women than men, ²⁹ , ³⁰ , ³¹ while there were also several studies reported that O₃ may have a more significant impact on stroke risk among men. ³² , ³³ Despite the observed sex‐specific differences in air pollution–related cardiovascular diseases, particularly stroke, the intricate interplay of physiological structure, hormones, metabolism, and psychosocial factors complicates drawing definitive conclusions from current evidence. Emerging evidence also indicated that socioeconomically disadvantaged populations exhibited heightened vulnerability to PM_2.5 exposure. Comparative analyses revealed that low‐income households and Black communities experience significantly elevated stroke risk at equivalent PM_2.5 exposure levels when contrasted with more affluent demographics. ³⁴ Contextual deprivation, defined as a multidimensional construct integrating neighborhood poverty indices, residential environmental quality, and employment opportunity metrics, represents the primary effect modifier in PM_2.5–stroke risk associations. Moreover, studies indicated that higher vegetable intake could reduce air pollution (PM_2.5, NO₂, and NO_x)–related all‐cause death, ³⁵ while alcohol intake increased the cardiometabolic risk from PM_2.5 and NO₂. ²⁷ A recent crossover study also noticed that even short‐term exposure to PM_2.5 enhanced the risk of stroke in susceptible populations with preexisting atrial fibrillation (AF), hypertension, diabetes, and hyperlipidemia. ³⁶ These studies indicate that certain population subgroups may be more susceptible to stroke triggered by air pollution. However, current evidence regarding the influence of certain factors, particularly sex differences, remains inconclusive. Therefore, additional research is needed to better identify vulnerable populations and develop more effective protective measures against air pollution–induced health damage.

Toxicological Studies

Several critical studies take the lead in revealing the role of air pollutants, especially PM, on the development and progression of ischemic/hemorrhagic injury to the rodent brain (Table 2). The middle cerebral artery occlusion (MCAO) model blocked the blood flow into the brain to reflect the cerebral infarction induced by ischemic stroke. In 2010, Sang et al first revealed that acute SO₂ inhalation could exacerbate the cerebral infarct induced by the MCAO procedure, accompanied by enhanced expression of vasoconstrictor and inflammatory mediators in the cortex. ³⁷ This study used fresh air to dilute SO₂ gas to a proposed dose (7 ± 0.78 mg/m³), and rats were exposed to SO₂ for 7 days (6 h/d) after an MCAO procedure for 180 minutes. Although this study provided preliminary evidence for SO₂‐related cerebrovascular effects, it failed to provide a proper reference supporting that the dose selection was relevant to SO₂ exposure in the real world, thereby limiting the extrapolation potential of these findings. A similar exposure procedure was also adopted for the inhalation of NO₂. The amplifying effects of ischemic stroke were also observed after acute exposure to NO₂ for 7 days, and further investigations indicated that NO₂ also impaired the structure of synapse in MCAO models, suggesting a potential risk in promoting vascular dementia after stroke. ³⁸ , ³⁹ The same research group also reported that PM₁₀ could enforce ischemic damage in an in vitro neural model with oxygen and glucose deprivation, and winter PM₁₀ samples with abundant polyaromatic hydrocarbons had the most significant impacts. ⁴⁰ In 2016, Liu et al provided the first laboratory evidence of the stroke exacerbation by nano‐sized PM in mice underwent MCAO, as reflected by elevated infarction volume and neurological deficit. ⁴¹ In addition, urban PM samples collected from Beijing could potentiate the movement disorder and edema in ischemic stroke mouse models induced by cortical photothrombosis, while not affecting the prognosis of stroke in mice with aryl hydrocarbon receptor knockout, indicating polyaromatic hydrocarbons in PM was responsible for these deteriorating effects. ⁴² A recent study also indicated that PM_2.5 exacerbated ischemic stroke in rats through dual mechanisms: directly impairing neuronal Akt/β‐catenin signaling and indirectly disrupting blood–brain barrier integrity via macrophage‐derived proteolytic factors. ⁴³ The identified crosstalk between perivascular macrophages and cerebral endothelium reveals a previously underappreciated amplification loop in pollution‐enhanced stroke pathogenesis. Nevertheless, this study used tail vein injection of PM_2.5 in rats, which delivers particles directly into the systemic circulation, thereby failing to recapitulate real‐world inhalation exposure scenarios. This methodological limitation may compromise the ecological validity of the findings.

Table 2.

Summary of Air Pollution–Induced Cerebrovascular Disease From Laboratory Studies

References	Pollutant	Model	Study design	Major outcomes
37	SO2	MCAO	Rats underwent MCAO for 180 min and then inhaled SO2 (7 mg/m3) 6 h/d for 7 d	SO2 exacerbated cerebral infarction and neuroinflammation caused by the MCAO procedure
38	NO2	MCAO	Rats underwent MCAO for 180 min and then inhaled NO2 (7 mg/m3) 6 h/d for 7 d	NO2 exacerbated cerebral infarction and neuroinflammation caused by the MCAO procedure
39	NO2	MCAO	Rats underwent MCAO for 180 min and then inhaled NO2 (5 mg/m3) 6 h/d for 7 d.	NO2 reduced synaptic plasticity of rats after ischemic stroke
40	PM10 collected from an urban area in Shanxi	OGD	Cells collected from the rat cortex were cultured with DMEM with low glucose (1 g/L) in a chamber with 5% CO2 and 95% N2 at 37 °C for 45 min to establish the OGD model and then exposed to PM10 (100 μg/mL) for 24 h	PM10 amplified the ischemic injuries in vitro OGD model
41	Nano‐sized PM was collected from an urban area in central Los Angeles	MCAO	Mice inhaled nano‐sized PM (<200 nm, 300–350 μg/m3) 5 h/d, 3 d/wk for 3 wks and then underwent MCAO for 35 min	Nano‐sized PM exacerbated cerebral infarction and neurological deficit caused by the MCAO procedure
42	Standardized urban PM (NIES CRM28)	Cortical photothrombosis	Mice with or without aryl hydrocarbon receptor knockout were intranasally administered with CRM28 (10 or 100 μg/10 μL) for 7 d, and then intraperitoneally injected with Rose Bengal (50 mg/kg) followed by a LED illumination for 25 min to induce ischemic stroke	CRM28 exposure potentiated movement disorder, neuroinflammation, and vasogenic edema
43	Standardized PM2.5 (NIST, SRM 2786)	MCAO and OGD	PM2.5 (6.34 mg/kg bw) was intravenously administered into the teil vein of mice. After 48 h of administration, mice underwent MCAO for 3 h. RAW264.7 cells were treated with PM2.5 (0, 0.1, 0.5, 2, and 8 μg/cm2) and the conditioned medium was collected. bEND.3 cells were exposed to conditioned medium for 24 h and then subjected to OGD for 8 h.	PM2.5 potentiated ischemic brain injury induced by MCAO through impairing the tight junction
44	Nano‐sized PM was collected from an urban area in central Los Angeles	CCH	Mice inhaled nano‐sized PM (<200 nm, 295–330 μg/m3) 5 h/d, 3 d/wk for 10 wks, and then underwent BCAS procedure to induce CCH 30 d before the end of exposure	Nano‐sized PM potentiated the white matter hypoperfusion and enhanced the BBB permeability induced by CCH.
45	Nano‐sized PM was collected from an urban area in central Los Angeles	CCH	Mice inhaled nano‐sized PM (<200 nm, 295–330 μg/m3) 5 h/d, 3 d/wk for 10 wks, and then underwent BCAS procedure to induce CCH 30 d before the end of exposure	Nano‐sized PM triggered demyelination, worsen the white matter hypoperfusion, and enhanced the BBB permeability induced by CCH
46	Standardized diesel exhaust (NIST SRM 2975)	CCH	Mice with or without TLR4 knockout inhaled diesel exhaust 5 h/d, 5 d/wk for 8 wks, and then underwent BCAS procedure to induce CCH 30 d before the end of exposure	Diesel exhaust enhanced the expression of dMBP, Iba‐1, 4‐HNE, and 8‐OhdG in CCH model.
47	PM2.5 collected by the real‐world exposure system located in Beijing	SHR	SHR rats inhaled PM2.5 (59.2 μg/m3) for 12 mo	PM2.5 induced cerebral microbleeds in SHR rats

4‐HNE indicates 4‐hydroxynonenal; BCAS, bilateral carotid artery stenosis; CCH, chronic cerebral hypoperfusion; CRM, certified reference material; dBMP, 4,4'‐dimethoxybenzophenone; LED, light‐emitting diode; MCAO, middle cerebral artery occlusion; NIES, National Institute for Environmental Studies; NIST, National Institute of Standards and Technology; OGD, oxygen and glucose deprivation; PM, particulate matter; SHR, spontaneous hypertensive; SRM, standard reference material; and TLR4, toll‐like receptor 4.

The chronic cerebral hypoperfusion model induced by bilateral carotid artery stenosis was widely approved to simulate white matter injury caused by ischemic cerebrovascular disease. Just as we mentioned in the previous text, several studies revealed that nano‐sized PM could intensify the white matter impairment induced by chronic cerebral hypoperfusion, and these synergistic effects could be explained by the shared mechanism of both PM and chronic cerebral hypoperfusion to trigger oxidative stress and neuroinflammation in the cortex. ⁴⁴ , ⁴⁵ , ⁴⁶ More interestingly, long‐term exposure to PM_2.5 was reported to induce cerebral microbleeds (a prevalent risk factor for stroke) in spontaneously hypertensive rats, in accordance with the continuous increase in blood pressure during the 12‐month exposure period. ⁴⁷ Although the current evidence preliminarily showed that air pollution could aggravate cerebrovascular injury, especially the pathological changes after ischemia, these results were mainly obtained from models with coexisting cerebral injury from surgical induction or combined with canonical risk factors such as hypertension, so it remained unclear from the laboratory perspective whether long‐term continuous exposure to air pollutants could directly induce acute cerebral events like stroke. Furthermore, current toxicological studies have predominantly focused on modeling the effects of air pollution on cerebral ischemia, while evidence remains scarce regarding its potential exacerbation of intracerebral hemorrhage. As previously mentioned, epidemiological studies have demonstrated a more pronounced association between air pollution and ischemic stroke, yet this observation has not been substantiated by laboratory investigations.

Direct Effects on the Cerebrovascular System

Translocation of PM to the Brain

PM could enter the human body through the respiratory tract, gastrointestinal tract, skin, and eyes, and the respiratory system was identified as the major target and predominant exposure pathway. Larger particles such as PM₁₀ are predominantly captured in the upper respiratory tract and effectively cleared via mucociliary action, whereas smaller particles (PM_2.5 and PM_0.1) exhibit higher alveolar deposition efficiency due to their ability to bypass upper airway defenses. Indeed, most published studies did not separate PM_2.5 from its smaller counterpart, PM_0.1, while recent findings indicated that those exogenous ultrafine particles may enter the bloodstream or even penetrate the BBB. ⁴⁸ Using inhalable gold nanoparticles with diameters ranged from 2 to 200 nm, Miller et al traced the fate of these particles by conducting a controlled exposure study. They revealed that after acute inhalation for 2 hours, these gold particles could be detected in both the blood and urine of healthy human participants, and nanoparticles with diameters <10 nm had greater translocation than the larger one. ⁴⁹ Another vital finding of this study was that after similar exposure protocols, gold nanoparticles could be found in the carotid plaques of patients subject to acute cerebrovascular events, providing valuable support for their entrance to the extrapulmonary organs. More intriguingly, Maher et al first reported the presence of exogenous magnetite nanoparticles (≤200 nm) in the human brain samples. These iron‐enriched particles were confirmed to originate from high‐temperature processes, particularly through frictional heating mechanisms as exemplified by brake pad wear. ⁵⁰ Similarly, after continuously exposed to PM for 24 weeks, ambient particles were observed by the scanning electron microscopy in the brain tissue of mice. ⁵¹ Based on these findings and previous detection of the ambient nanoparticles in the olfactory bulb of residues from Mexico cities, it was speculated that PM with particle sizes ≤200 nm may directly enter the brain through the olfactory nerve (Figure 2). ⁵² , ⁵³ Taken together, although additional validation was required for the precise route, it was concluded that PM could enter the cerebral system and directly interact with the cerebral vessels.

Figure 2. Schematic illustration of air pollution–induced direct effects on the cerebrovascular system.

PM first translocated to the brain through the olfactory bulb, then PM induced microglial activation to trigger neuroinflammation, which resulted in endothelial dysfunction and the loss of tight junction. This figure was created using sources from the Servier Medical Art (https://smart.servier.com). BBB indicates blood–brain barrier; and PM, particulate matter.

Oxidative Stress

Oxidative stress is an imbalance of the redox system caused by the accumulation of reactive oxygen species (ROS), consuming antioxidants and eventually leading to oxidative damage. Once internalized by cells, PM and other chemicals or metals on their surfaces could generate ROS through the disturbance of the redox cycling. Oxidative stress was the most prevalent mechanism for PM‐induced toxicity and regarded as a KE linking air pollution to the cardiovascular effects. The role of oxidative stress and ROS‐related signals was extensively documented in previous review, and ROS generation was identified as a molecular initiating event for endothelial dysfunction, vascular inflammation, calcification, fibrosis, and cardiac dysfunction. ¹¹ , ¹² , ¹³ More importantly, ROS generation is also a prevalent toxic indicator of PM when they directly act on microglia. Recent studies confirmed that PM could induce oxidative stress in human microglial cells and microglia‐like cells (BV2 cells), which subsequently triggered inflammatory responses via the toll‐like receptor 4/nuclear factor‐κB pathway. In contrast, pretreatment with antioxidants such as acetylcysteine and MitoTEMPO could alleviate adverse effects from PM exposure. ⁵⁴ , ⁵⁵ Interestingly, in a recent study using induced pluripotent stem cell–derived microglia, PM derived from diesel (EN590) containing lower sulfur reduced ROS production, while PM derived from compressed natural gas still induced an ROS burst. ⁵⁶ Although this observation suggests that ROS generation may be affected by the composition of PM, it should be confirmed which components are responsible for this difference. A comprehensive study revealed that diesel‐derived PM_2.5 induced neurotoxicity in mice and BV2 cells could be attenuated by acetylcysteine treatment, indicating that PM_2.5 may induce oxidative stress and microglia activation via its metal components. ⁵⁷ Therefore, although air pollution may not always cause direct pathologic changes in the brain, oxidative stress can be a ubiquitous precondition for further injury to the brain.

Microglial Activation

Inflammation in the CNS could be a general consequence triggered by oxidative stress, and PM was widely documented to induce neuroinflammation through activating the inflammatory signaling pathway. As the predominant immune cells in the CNS, microglia could protect the neurons and promote tissue regeneration in acute cerebrovascular events, but prolonged activation of microglia caused chronic inflammation and promoted the progression of stroke. Microglia were the first cells to respond to the CNS injury, and once they received the pathological signals, they could be similarly activated as other immune cells, resulting in 2 completely opposite phenotypes in function, namely, M1 (proinflammatory) and M2 (anti‐inflammatory) microglia. ⁵⁸ Most existing evidence suggests that PM induces proinflammatory activation of microglia to induce neural damage. Ultrafine particles were reported to induce microglia activation (characterized by Iba‐1 ⁺ microglia) through the NLRP3 signaling pathway, while such effects were mitigated in Nlrp3 ^−/− mice. ⁵⁹ The role of toll‐like receptor 4 signaling pathway was recently confirmed by an in vivo study, as microglia‐specific toll‐like receptor 4 knockout could attenuate the joint effects caused by diesel‐derived PM and chronic cerebral hypoperfusion. ⁴⁶ Moreover, diesel‐derived PM could also amplify microglial inflammation through impairing the expression of the TREM2 protein. ⁶⁰ Interestingly, the mRNA expression of Tnf was only upregulated in Trem2 ^+/+ mice after PM exposure, while Il1b was only upregulated in Trem2 ^−/− mice. In vitro exposure of diesel‐derived PM could induce neuron death through microglia activation, while such effects were attenuated by antibiotic minocycline and PPAR‐γ agonist (pioglitazone). ⁶¹ One of the important observations in this study was that minocycline only exhibited protective effects when neurons were cocultured with microglia, suggesting that microglia activation should be an essential pathway for PM to induce neurological injury. In vitro exposure of diesel‐derived PM could amplify the upregulation of tumor necrosis factor‐α (TNF‐α) and nitrite in microglia after stimulated by lipopolysaccharide, even at a nonneurotoxic concentration (5 μg/mL). ⁶² SO₂ consecutive inhalation (14 mg/m³, 6 h/d) for 7 days induced microglial activation in the mouse brain and enhanced the expression of TNF‐α and interleukin‐1β, while treatment with endocannabinoids, the agonist of cannabinoid receptors could attenuate SO₂‐induced neuroinflammation. ⁶³ However, the exposure concentration of 14 mg/m³ used in this study substantially exceeds typical ambient SO₂ levels, potentially limiting the extrapolation of these findings to real‐world environmental exposure scenarios. These studies confirm that microglia activation is a KE in air pollution‐induced neurotoxicity, while targeting the inflammatory signaling pathway can be a promising strategy against these effects.

Increased BBB Permeability

Brain function requires cooperation by various cell types including endothelial cells, smooth muscle cells, pericytes, neurons, and microglia to formulate the neurovascular unit. A recent study found that PM_2.5 could potentiate ischemia‐induced neurovascular unit damage and impair tight junction in rat brain. ⁴³ BBB is a highly selective semipermeable membrane barrier in the cerebral vessels consisting of endothelial cells and astrocytes with tight junctions. BBB protects the CNS from harmful substances (such as toxins and pathogens) and fluctuating blood components (such as hormones and ions), while maintaining the homeostasis of the microenvironment in the neurovascular unit. During the progression of stroke, the BBB could be disrupted by prolonged oxidative stress and neuroinflammation, resulting in the release of immune cells, inflammatory mediators, and plasma proteins into the CNS, and eventually exacerbating neuronal injury and cerebral edema. ⁶⁴ Although it remained controversial whether PM could directly penetrate the BBB, increased evidence suggested mixed emissions from diesel or traffic exhaust could enhance the BBB permeability in rodent brain through reducing tight junction–associated proteins such as claudin‐5 and occludin in cerebral vessels. In contrast with these findings, Huuskonen et al reported that although exposure to PM ≤200 nm did not change the BBB permeability, it could exacerbate the BBB damage after cerebral hypoperfusion caused by bilateral carotid artery stenosis. ⁴⁵ P‐glycoprotein is an ATP‐dependent pump regulating efflux transportation in the BBB and is generally influenced by stroke and neurodegenerative diseases. Further mechanistic investigation indicated that diesel‐derived PM could significantly upregulate P‐glycoprotein in cerebral capillaries of mice through oxidative stress and activation of the JUN N‐terminal Kinase signaling pathway. ⁶⁵ More interestingly, serum collected from mice inhaled with traffic exhaust could also enhance the expression of P‐glycoprotein in in vitro BBB coculture models, suggesting that the BBB injury could also be an indirect effect caused by circulating mediators. ⁶⁶ Although air pollutants are reported to induce BBB disruption, mechanistic validation is still lacking to prove whether this event is directly triggered by microglia activation and neuroinflammation.

Systemic Inflammation

Proinflammatory Mediators

Cerebrovascular disease could be a systemic effect caused by a series of changes in the cardiovascular system, especially a general consequence of altered hemodynamics, hypertension, and thrombosis. Considering that the lung should be the major target organ for most air pollutants, another vital theory for their cerebral effects was the systemic inflammation, which highlighted the association between pulmonary inflammation and cardiovascular disease (Figure 3). This hypothesis suggested that air pollutants first interacted with the pulmonary immune cells, thereby triggering the release of proinflammatory cytokines into circulation, resulting in endothelial dysfunction, procoagulant state, and even atherosclerosis. Macrophages served as the initial defender in the respiratory tract against air pollution, they actively engulfed and phagocytosed dust, smoke, pollen, or other airborne substances to prevent lung injury. Both in vivo and in vitro studies confirmed that PM‐induced macrophage activation through ROS‐dependent activation of the NLRP3 and PI3K/mTOR signaling pathway, while treatment with ROS scavengers could mitigate inflammation. ⁶⁷ , ⁶⁸ In accordance with these laboratory findings, population‐based studies indicated that 24‐hour exposure to PM_2.5 was associated with an elevated circulating level of proinflammatory mediators including monocyte chemoattractant protein‐1, interleukin‐1β, interleukin‐6, and TNF‐α in healthy nonsmoking volunteers, and 2‐week exposure to O₃ was associated with increased serum levels of interleukin‐1β, interleukin‐8, interferon‐γ, and TNF‐α in healthy participants. ⁶⁹ , ⁷⁰ These findings support that PM can induce macrophage activation via ROS‐related signaling, and the proinflammatory mediators secreted by macrophages may contribute to systemic inflammation in the cardiovascular system.

Figure 3. Schematic illustration of air pollution triggered systemic inflammation from the respiratory to cardiovascular system.

PM initially triggered proinflammatory polarization of macrophages in the lung, resulting in the release of inflammatory cytokines into the circulation. PM translocated in the blood could also induce endothelial cell death and reducing NO production via redox imbalance and ER stress. Thereafter, endothelial cell dysfunction further activated the clotting cascade and enhanced platelet activation, which subsequently caused thrombosis. On the other hand, circulating inflammatory mediators and PM‐induced dyslipidemia cooperated in the foam cell formation and finally resulted in atherosclerosis. This figure was created using sources from the Servier Medical Art (https://smart.servier.com). CHOP, C/EBP homologous protein; ER, endoplasmic reticulum; NF‐κB, nuclear factor‐κB; PM, particulate matter; ROS, reactive oxygen species; sP‐selectin, soluble P‐selectin; and vWF, von Willebrand factor.

Endothelial Dysfunction

Endothelial cells form a single layer lining the interior of blood vessels, playing a crucial role in maintaining vascular homeostasis and controlling material exchange. Circulating proinflammatory mediators such as TNF‐α, interleukin‐1β, interleukin‐6, and interleukin‐8 disrupt endothelial homeostasis, causing increased vascular permeability, leukocyte adhesion, and reduced vasodilatation. Under prolonged inflammatory stimulation, endothelial dysfunction could further result in senescence and death of endothelial cells, a widely recognized pathological basis for atherosclerosis. As these weakened cells succumb to the inflammatory onslaught, they detach from the vessel wall, entering the bloodstream as cellular debris, which could further drive thrombosis by interacting with platelets and promoting coagulation. Endothelial dysfunction induced by PM may be a consequence from systemic inflammation or directly caused by PM entering the circulatory system. Laboratory evidence of PM‐related endothelial dysfunction is extensively detailed in previous AOPs. ¹¹ , ¹² In accordance with these findings, circulating microparticles derived from activated or apoptotic endothelial cells were also elevated by PM_2.5 exposure in healthy nonsmokers. ⁶⁹ The most recent evidence also suggested that even short‐term exposure to ultrafine particles induced molecular changes related to systemic inflammation (TNF‐α, interleukin‐6, and interleukin‐1β) and endothelial dysfunction (endothelin‐1 and endothelial nitric oxide synthase) in healthy human participants. ⁷¹ Although numerous studies have confirmed that direct PM exposure can induce endothelial dysfunction through endoplasmic reticulum stress, autophagy dysfunction, inflammatory signaling pathways, and ferroptosis, ¹¹ the relative contributions of systemic inflammation versus direct cytotoxic effects on endothelial cells remain unclear. Furthermore, while systemic inflammation and endothelial dysfunction often co‐occur in animal models, the causal relationship and temporal sequence between these 2 phenomena have not been confirmed.

Thrombosis

The integrity of endothelium maintained a nonadherent monolayer at the physiological state to prevent abnormal activation of thrombosis, while endothelial damage caused exposure to matrix proteins and resulted in activation of the clotting cascade. Persuasive evidence indicated that air pollution could induce prothrombotic and antifibrinolytic status. ⁷² Ambient PM_2.5 was reported to induce platelet activation and aggregation in healthy young adults, as reflected by increased expression of soluble P‐selectin and von Willebrand factor. ⁷³ Similar effects were even more prominent in overweight adults, indicating an important role in obesity‐related inflammation. ⁷⁴ Another convincing evidence was that short‐term reducing PM pollution during the Beijing Olympic period was associated with decreased soluble P‐selectin and von Willebrand factor. ⁷⁵ Either intrinsic or extrinsic coagulative pathways promoted the transaction of prothrombin to thrombin, which in turn catalyzed the conversion of fibrinogen to fibrin that served as the structural basis for clot formation. ⁷² Acute exposure to air pollutants including PM₁₀, CO, NO₂, and O₃ for 0 to 96 hours was generally documented to associate with increased platelet activation and thrombin generation but not fibrinogen levels. ⁷⁶ More interestingly, ex vivo exposure to diesel‐derived PM could enhance clot formation in plasma from patients with stroke, and similar effects were also observed in cerebral ischemic mice after acute and chronic instillation with PM. ⁷⁷ Although the link between air pollution and thrombosis is relatively clear, the main upstream cause of this KE remains ambiguous, as it is still questionable whether coagulation results from systemic inflammation, endothelial dysfunction, or both. An important study suggested that dietary supplementation with olive oil could attenuate PM‐induced endothelial dysfunction and increase fibrinolysis in healthy participants. ⁷⁸ However, this evidence remains insufficient to support the causal relationship between these 2 KEs.

Atherosclerosis

Another detrimental consequence of endothelial dysfunction could be atherosclerosis, and air pollution was reported to induce atherosclerosis in both animal and population studies. Based on the ApoE ^−/− mouse model on a high‐fat diet, numerous studies indicated that long‐term exposure to PM could significantly promote atherosclerotic plaque formation. ⁷⁹ , ⁸⁰ , ⁸¹ PM_2.5 was also reported to reduce collagen content and fibrous cap thickness in mice, but enhance lipid deposition, eliciting that PM_2.5 could exacerbate plaque vulnerability. ⁸⁰ In vivo studies reported that mitigating macrophage M1 polarization with melatonin and attenuating endothelial dysfunction with statins could reduce PM‐related atherosclerosis. ⁷⁹ , ⁸¹ More results from epidemiological studies also supported the causal relationship between air pollution and atherosclerosis‐related diseases, and the dose–response curve of those diseases was almost linear, with an especially steep slope at low concentrations and no establishing threshold. ⁸² As the most direct surrogate effect for atherosclerosis and an important predictor for future cardiovascular disease, coronary artery calcification was widely reported to be associated with long‐term PM_2.5 exposure, even at a mean exposure level below 15 μg/m³. ⁸³ A more recent study indicated that 10‐year exposure to PM_2.5 at an even lower level (6.2 μg/m³ in average) was still associated with increased noncalcified plaques. ⁸⁴ In accordance with laboratory findings, Yang et al reported that elevated PM_2.5 concentration was associated with the occurrence of high‐risk plaque, as reflected by enhanced fibrofatty, necrotic core, and total plaque volume. ⁸⁵ The formation of atherosclerotic plaques will directly cause vascular stenosis and limited blood flow, and the rupture of plaques may also cause thrombosis, which imposes a high risk for acute cerebrovascular disorders. Therefore, air pollution–related atherosclerosis may be the core pathological basis of consequent cerebrovascular diseases.

Neuroendocrine Dysregulation

Activation of the Sympathetic Nervous System

Cumulative evidence indicated that the inhalation of air pollutants may activate pulmonary sensory receptors that stimulate the autonomic nervous system through the nodose and jugular ganglia, which could then modulate respiratory and cardiovascular function (Figure 4). Transient receptor potential (TRP) receptors are widely distributed in pulmonary sensory nerves and act as environmental sensors. After intratracheal instillation, diesel‐derived PM was reported to activate pulmonary receptors including TRPV1 and TRPA1 in mice and rats. In contrast, the inhibition of TRPV1 could attenuate elevated blood pressure and arrhythmia, while treatment with TRPA1 antagonist could also reduce sensitivity to arrhythmia. ⁸⁶ , ⁸⁷ More importantly, Hazari et al primarily reported that the inhibition of TRPA1 could reverse diesel‐derived PM‐induced activation of sympathetic tone, as reflected by heart variability. ⁸⁷ Based on these findings, current scientific consensus indicates that airborne pollutants predominantly exert their neuroendocrine effects through pulmonary sensory nerve activation, which subsequently engages vagal pathways. This neural transmission is mediated via brainstem nuclei before reaching higher integrative centers, particularly the hypothalamus, where it initiates the hypothalamic–pituitary–adrenal) axis and sympathetic–adrenal–medullary axis activation, ultimately leading to heightened sympathetic tone. ⁸⁸ As demonstrated by in vivo studies, systemic inhibition of β1 adrenoreceptor could attenuate PM‐induced cardiac injury, ⁸⁶ and blockage of sympathetic but not parasympathetic activity attenuated PM‐related sensitivity to arrhythmia. ⁸⁷ Intriguingly, Rankin et al reported that acute inhalation of diesel‐derived PM could directly increase the sympathetic outflow within 10 minutes in healthy humans. ⁸⁹ However, there were also inconsistent findings indicating that combined ultrafine particle and O₃ exposure increased circulating norepinephrine levels by blocking the clearance rather than increasing the sympathetic activity. ⁹⁰

Figure 4. Schematic illustration of air pollution enhanced activity of the sympathetic nervous system and increased blood pressure.

PM primarily triggered sensory receptors such as TRPA1 and TRPV1 in the lungs and then activated the sympathetic nervous system. Afterward, enhanced sympathetic activity stimulated the HPA axis through enhanced norepinephrine generation, and these 2 systems coordinated to enhance the production of stress hormones. These hormones cause vasoconstriction and an increased heart rate, which eventually lead to hypertension. This figure was created using sources from the Servier Medical Art (https://smart.servier.com). HPA indicates hypothalamic–pituitary–adrenal; PM, particulate matter; and TRP, transient receptor potential.

Increased Stress Hormone

Both the sympathetic–adrenal–medullary and the hypothalamic–pituitary–adrenal axis control the release of stress hormones such as cortisol, adrenaline, and noradrenaline in response to stress, while prolonged activation has been extensively reported to be associated with cardiovascular diseases in aging and obesity. The enhanced production of norepinephrine from the sympathetic nervous system could also stimulate corticotropin‐releasing hormone from the hypothalamic–pituitary–adrenal axis, and these 2 interconnected mechanisms may coordinate together in air pollution‐induced stress hormone elevation. A randomized controlled trial conducted by Li et al provided solid evidence that increased PM_2.5 exposure within 9 days was associated with elevated circulating level of cortisol, cortisone, epinephrine, and norepinephrine in healthy nonsmokers. ⁹¹ Another longitudinal study from China also reported the association between PM_2.5 and circulating level of stress hormone, and further analysis found that metal constituents (Zn, Mn, Cu, Fe, etc) but not carbon in PM_2.5 showed positive associations with corticotropin‐releasing hormone, adrenocorticotropic hormone, and cortisol. ⁹² In addition, long‐term observation revealed that both annual NO_x and PM_2.5 exposure were associated with increased urinary epinephrine level, while only increased PM_2.5 exposure was correlated with enhanced urinary dopamine. ⁹³ These findings indicated that air pollution–stimulated stress hormones may be an explanation for their impact on cardiovascular function and build up a link from alteration of the autonomic nervous system to induce heart rate elevation or vasoconstriction. Nevertheless, current evidence only indicates that air pollution can elevate circulating levels of stress hormones. However, as previously mentioned, this effect may stem from the activation of the sympathetic–adrenal–medullary axis and the hypothalamic–pituitary–adrenal axis, or alternatively, from the ability of air pollution to inhibit the clearance of stress hormones in circulation. ⁹⁰ The causal relationship still requires further research for validation.

Hypertension

Overriding of the sympathetic–adrenergic axis has been generally regarded as a promising therapeutic target for hypertension, which was among the most dominant and modifiable risk factors for stroke. ¹⁴ Sufficient evidence from longitudinal and observational studies also indicated an increase in blood pressure in response to either acute or chronic PM_2.5 exposure, and randomized controlled trials suggested that personal levels reduction in air pollution could improve blood pressure. ⁹⁴ In an elegant study designed by Ying et al, inhalation of PM_2.5 for consistently 6 months was found to increase blood pressure and urinary norepinephrine in mice, while treatment with α_2a agonist (an inhibitor for sympathetic activity) could significantly release blood pressure, suggesting a direct link between the sympathetic tone and air pollution–mediated hypertension. ⁹⁵ Further analysis for components indicated that black carbon and soil particles in PM_2.5 showed positive correlations with blood pressure and hypertension prevalence in a rural area of China. ⁹⁶ In summary, as one of the most significant risk factors for stroke, hypertension may represent one of the primary pathways through which air pollution contributes to stroke incidence. Moreover, air pollution (PM_2.5, PM₁₀, NO₂, and NO_x) is consistently associated with incidence of AF, another well‐defined risk factor for cardioembolic stroke. ⁹⁷ Although the mechanisms for AF are not fully established, hypertension and arrhythmia induced by activation of sympathetic tone may play a key role in the onset of AF.

Clinical Implications and Perspective

Based on all available evidence from air pollution, we proposed a theoretical framework for air pollution–induced cerebrovascular disease. Primarily, PM in air pollution can directly translocate to the brain, triggering neuroinflammation and compromising BBB integrity. This may represent a key pathological basis for the development of cerebrovascular diseases and further CNS system damage. The BBB dysfunction induced by air pollution can affect both ischemic and hemorrhagic stroke and further lead to a poor neurological outcome. More intriguingly, during the initiation and progression of ischemic stroke, BBB disruption exacerbates brain edema and increases the risk of hemorrhage, which may lead to a hemorrhagic transformation and limit the efficacy of thrombolytic treatment. ⁶⁴ Additionally, air pollution can induce thrombosis and atherosclerosis through respiratory–cardiovascular inflammatory responses, which may have a generally larger impact on ischemic stroke. Ischemic stroke accounts for 62% of all stroke incidence, and about 13% of ischemic stroke is identified to be a consequence from large‐artery atherosclerosis. ⁹⁸ Moreover, current evidence also suggests that air pollution may elevate systemic blood pressure through neurohumoral regulation, which may affect all stroke subtypes, with a slightly larger effect on hemorrhagic stroke. Hypertension is the leading modifiable risk factor of stroke incidence and death, which is associated with ≈50% of ischemic stroke and 70% of hemorrhagic stroke. ⁹⁹ Besides, cardioembolic events such as AF are involved in 27% of ischemic stroke, either atherosclerosis, hypertension, or arrhythmia induced by air pollution increased the risk of AF. ⁹⁸ These findings underscore the potential role of cardiovascular alterations induced by air pollution in subsequent cerebrovascular events, highlighting the importance of studying cardio‐cerebrovascular multimorbidity as a crucial area of future research. Following these discussions, we will then summarize the direct evidence supporting the impact of air pollution on cerebrovascular disease, which demonstrates a direct association between air pollution and stroke incidence and death.

Air pollution stands out from other environmental hazards due to its ubiquitous and lifelong exposure through respiration. This makes it an unavoidable risk factor for populations across age, sex, and geographic location. Reducing air pollution holds significant clinical value in mitigating major causes of death such as cardiovascular and cerebrovascular disease. Sufficient epidemiological studies supported air pollution should be a general risk factor for either death or incidence of cerebrovascular events, especially ischemic stroke. As we emphasized in this review, air pollution–related impact on cerebrovascular disease should be a comprehensive consequence from BBB disruption, systemic inflammation from the respiratory to the cardiovascular system, and autonomic dysregulation, emphasizing the role of cardio‐cerebrovascular multimorbidity in this process. In China, there were >300 million people with combined cardio‐cerebrovascular conditions, and >20% of patients with coronary artery disease developed cerebrovascular stenoses. ¹⁰⁰ According to the GBD study, stroke and ischemic heart disease were 2 major causes of PM_2.5‐related death for the population aged ≥54 years, indicating that air pollution imposed the highest burden in cardio‐cerebrovascular disease among older individuals. ¹⁰¹ Indeed, cerebrovascular disease shares similar risk factors with cardiovascular disease, including aging and obesity, and air pollution imposes a synergistic effect with these canonical risk factors to exacerbate pathological changes. Therefore, future studies on air pollution should consider the cardiovascular and cerebrovascular systems as intrinsically connected integrity, and the proposed mechanisms in this review were generally based on findings from diverse models and air pollution samples, which required further confirmation by further investigations.

The AOP framework indicated that cardiovascular alterations such as thrombosis, atherosclerosis, and hypertension were upstream key events before stroke; thus, it was proposed that patients with those preexisting cardiovascular malfunctions were at high risk for air pollution–induced cerebrovascular disease. Currently, clinical treatment options for stroke remain limited and rely heavily on timely intervention following acute symptom onset. Consequently, stroke prevention is the most crucial approach in mitigating long‐term death and disability. Emerging evidence highlights the significant role of cardio‐cerebrovascular multimorbidity in acute cerebrovascular events. For high‐risk individuals residing in areas with elevated air pollution levels, clinicians should prioritize early detection and management of preexisting cardiovascular pathologies, such as atherosclerosis and thrombosis. Promptly advising these patients to avoid further exposure to air pollution and other established risk factors can effectively reduce the incidence of stroke. Moreover, epidemiological studies highlighted that even at exposure levels below the EU limitations or WHO interim levels, air pollutants, especially PM_2.5, could still increase incidence and death from stroke. These findings suggest that continued efforts to reduce air pollution at the global level are essential and the implementation of new WHO AQG limits are beneficial, but more immediate actions are needed to mitigate the health risks posed by air pollution, particularly for vulnerable populations.

For these high‐risk individuals, avoiding prolonged strenuous exercise in areas with high air pollution remains a primary preventative measure. Meanwhile, technological interventions, such as high‐efficiency particulate air filters, have demonstrated significant efficacy in reducing PM concentrations in indoor environments by 40% to 72%. ¹⁰² Residential air cleaners are recommended for reducing indoor air pollution derived from both indoor and outdoor sources. ¹⁰³ Recent human intervention trials using 3M Filtrate air purifiers (3M, Maplewood, MN; designed specifically for PM removal) have demonstrated that high‐efficiency particulate air filtration can effectively mitigate PM‐mediated cardiopulmonary effects, particularly through reducing abnormal sympathetic nervous system activation. ⁹¹ , ¹⁰⁴ While these devices show limited efficacy against gaseous pollutants, their selective PM reduction capacity provides compelling evidence that indoor particulate filtration alone can yield measurable health benefits. When outdoor activities are unavoidable, masks often become the only means of protection. Wearing N95 or N99 masks has been proven to reduce PM inhalation effectively, but their protective effects are contingent upon proper fit and correct wear. Sustained mask use, however, may exacerbate preexisting symptoms in individuals with compromised cardiopulmonary function. ¹⁶ In addition, laboratory evidence indicated that antioxidants such as acetylcysteine, MitoTEMPO, and melatonin may be beneficial in attenuating PM_2.5‐related cardiovascular toxicity, ⁵⁴ , ⁵⁵ , ⁷⁹ but no clinical evidence can support their protective effects. Of note, a large cohort study suggested that for older adults (aged >60 years), statin use significantly reduced stroke risk across varying PM₁₀ and PM_2.5 exposure levels. ¹⁰⁵ Among residents living in relatively higher PM_2.5 (>25 μg/m³) and PM₁₀ (>50 μg/m³) environments, statin users had 17% and 20% reductions in stroke incidence compared with nonusers, respectively. In summary, there remains a dearth of evidence‐based interventions to effectively mitigate the heightened risk of stroke posed by air pollution in high‐risk individuals. There is an urgent need for robust research, particularly randomized controlled trials, to demonstrate the benefits of air pollution reduction on cardio‐cerebrovascular multimorbidity and to develop more efficient and practical protective measures.

Sources of Funding

This work was supported by the Beijing Natural Science Foundation (JQ24047).

Disclosures

None.