The World Health Organization (WHO) estimates seven million premature deaths worldwide every year due to ambient air pollution (World health statistics, 2021). Extensive epidemiological evidence indicates that not only the respiratory system but almost every organ of the body is affected by polluted air exposure. Indeed, smaller pollutants that arise in the lungs can penetrate the bloodstream reaching the entire body, thus inducing cardiovascular injury, metabolic disorders, systemic inflammation, and carcinogenicity (Franchini and Mannucci, 2011; Rao, 2018). Recent evidence also indicates that air pollution aggravates coronaviruses’ epidemics, such as SARS and COVID-19, with greatest effects in urban areas, where emission levels are highest (Hutter et al., 2020; Cascetta et al., 2021; Salgado et al., 2021).

The outdoor air pollution—especially by PM_2.5—is deemed to be responsible for about 3.3 million premature deaths (Lelieveld et al., 2015), with accumulating evidence to indicate that the greatest number is related to cardiovascular diseases (CVDs) (Tofler and Muller, 2006; Brook et al., 2010). In Europe, the 45% of the mortality rate is caused by CVDs, which accounts for the 37% within the 28 countries of the European Union (Lelieveld et al., 2015; Wilkins et al., 2017). Furthermore, long-term PM_2.5 inhalation might result in endothelial injury, vascular homeostasis dysregulation and inflammation, increased coagulation-thrombosis risk, atherosclerosis, and hypertension, effects that could accelerate cardiovascular disease or generate negative cardiovascular events (Cui et al., 2016; Chen et al., 2018; Haberzettl et al., 2018).

In this context of endothelial dysfunction or injury, the endothelial progenitor cells (EPCs) play an essential role, as central regulators of vascular regeneration, angiogenesis, and reendothelialization, which facilitate to vascular repair (Jian et al., 2018; Bayraktutan, 2019). Since the exposure to ambient fine particles leads to cardiovascular injury and, at the same time, defects in vascular repair and regeneration (Chen et al., 2018), it is of common interest to understand how PM_2.5 affects the number and the functionality of EPCs.

In this review, we summarize the mechanisms by which PM exposure alters EPCs health and how it affects vascular repair following exposure-related cardiovascular injury.

In relation to particle size, environmental particulate matter is generally classified in PM₁₀ coarse, PM_2.5, and ultrafine particles (UFPs), characterized by an aerodynamic diameter of 10–2.5 µm, <2.5 µm, and <0.1 µm, respectively (Brook et al., 2010). Urban PM has a varied and complex composition, displaying elemental and organic carbon species (PAHs, nitro-PAHs, alkenes, etc.), especially from a major part of combustion-derived PM. Another important component is the non-carbon one, represented by various minerals’ dusts, sea salt, ammonium, nitrates, and sulfates. Additionally, the surface of PM may accumulate small amounts of biological materials (i.e., endotoxins), which are likely to be involved in airway inflammation and other aspects of the pathophysiological response (Miller and Newby, 2020).

In terms of toxicity, smaller size particles are considered of particular importance for health since they exert the greater effects due to their large reactive surface area and the ability to be inhaled deeply in the alveoli of the lungs (Ohlwein et al., 2019). Among the common fine particle air pollutants, PM_2.5, containing redox-active transition metals, quinones, and secondary organic aerosols, are mostly generated by the human combustion of fossil fuels (from industry processes, vehicle-exhaust emissions, and power generation) and display the longest atmospheric lifetime (Brook et al., 2010; Lakey et al., 2016). Since not filtered by the respiratory tract, these particles have been proposed to affect the cardiovascular system by reaching the terminal bronchioles via inhalation, entering alveoli, penetrating biological membranes, and inducing an inflammatory response in the lung, with the release of inflammatory mediators that enter the bloodstream (Miller and Newby, 2020).

Among the World’s population, the 91% lives in places where air pollution levels exceed the WHO guidelines limits, set at 5 µg/m³ for fine particulate matter PM_2.5 annual mean (Table 1). The World Health Organization attributes the 58% of outdoor air pollution-related premature deaths to stroke and ischemic heart disease, the 18% due to respiratory disease, and the 6% due to lung cancer (World health statistics, 2021).

Endothelial Progenitor Cells (EPCs) derive from the bone marrow, which are retained via adhesion molecules (i.e., CXCR4) or through interactions between α4β1-integrin and VCAM-1. EPCs originate from a primitive, undifferentiated hematopoietic and vascular cell precursor, circulate in the peripheral blood, and are implicated in neo-angiogenesis (Werner et al., 2005; Singh et al., 2021).

Despite EPCs exact phenotypic identity, origin, and location are debated (Fadini et al., 2012), flow cytometry and immunohistochemistry are the most commonly used techniques for their identification. However, it is difficult to accurately isolate EPCs based on cell surface markers they express because most of them are co-expressed by other endothelial or hematopoietic cells. Thus, the best option for EPCs detection seems the employment of a panel of antibodies targeting markers for hematopoietic cells, immaturity, stemness, and endothelial maturity (CD45, CD133, CD34, and KDR, respectively). In this way, it is possible to better discriminate between endothelial-committed EPCs (CD34 + CD133 + KDR + CD45⁻, CD34 + KDR + CD45⁻, and CD133 + KDR + CD45⁻) and undifferentiated EPCs (CD34 + CD133 + CD45⁻, CD34⁺,CD45-, and CD133 + CD45⁻) (Bayraktutan, 2019).

Consequent to vascular injury, EPCs cells mobilize from the bone marrow into peripheral blood, in response to biochemical stimuli (VEGF, SDF-1α), for example, in the case of ischemic injury (Bayraktutan, 2019; Singh et al., 2021). EPCs are also stimulated to migrate into the circulation upon hypoxic conditions by interactions between CXCR4 and its antagonist SDF-1a or upon matrix metalloproteinase-9 (MMP-9)-mediated release of the soluble c-Kit ligand (Heissig et al., 2002; Petit et al., 2007; Singh et al., 2021). After leaving the bone marrow, EPCs reach the site of endothelial injury where they attach and promote angiogenesis and revascularization by differentiating into mature, functional endothelial cells, or by paracrine stimulation of the existing endothelium to proliferate and migrate (Asahara et al., 1997; Singh et al., 2021). In brief, the EPCs’ mobilization to the vascular injury is influenced by physical factors, such as vascular structure and density, and flow rate, and, also, the expression of cell surface adhesion molecules, in particular VCAM-1 and ICAM-1. Moreover, the increased availability of cytokines, such as IL-6 and GM-CSF (granulocyte-macrophage colony-stimulating factor), contributes to the regulation of EPCs’ counts and behavior, for example, after ischemic injury (Orlic et al., 2001; Fan et al., 2008).

Unsurprisingly, the presence of immature circulating cells in the peripheral blood is considered a marker of organism’s regenerative capacity; therefore, several clinical trials have been designed to increase EPCs’ number at the site of tissue damage (Assmus et al., 2002; Wollert et al., 2004). The EPC-based therapies attract a lot of interest because of the peculiar ability of these cells to detect and repair endothelial damage and to differentiate into other cell lines to promote vasculogenesis, angiogenesis, and neurogenesis after stroke injury (Sekiguchi et al., 2009).

Werner et al. demonstrated the predictive role of CD34 + KDR + circulating EPCs in the occurrence of cardiovascular events and death from cardiovascular causes. They proved that a single measurement of CD34 + KDR + EPCs may help to identify patients with increased cardiovascular risk, predicting cardiovascular outcomes in patients with coronary artery disease. A strongly higher incidence of cardiovascular causes-related death was observed in patients with low baseline levels of EPCs during an observational period of 12 months (Werner et al., 2005).

Several experimental and clinical studies have also shown the EPCs’ involvement in improving revascularization in ischemia models (i.e., hindlimb ischemia and myocardial ischemia), in promoting endothelial health in restenosis and renal failure, and play a role in the pathogenesis of coronary disease, despite in this context their exact role remains to be determined (Werner et al., 2005; Thum et al., 2006; Groleau et al., 2010).

Several epidemiological studies positively associate air pollutants exposure with CVDs’ development risk. In particular, the urban PM_2.5 have been attributed vascular endothelial dysfunction and increased inflammation, which partially promote coagulation-thrombosis and ischemic risk, atherosclerosis, and hypertension, thus promoting and/or accelerating cardiovascular events. PM_2.5 prevalently exert their effects via oxidative stress and inflammation, and their ability to easily translocate to the blood circulation could account for the widespread effects of these particles around the body; however, the mechanisms remain not completely understood. PM_2.5 induce VECs’ toxicity and affect their physiological functions, also regulating a set of endothelium-related biomarkers including EPCs. Taken together, the reviewed studies demonstrate that PM_2.5 exposure leads to EPCs’ dysfunction and altered homeostasis, which in turn contribute to the increased CVDs’ risk. Thus, EPCs’ level and functionality may represent a sensitive biomarker of endothelial injury caused by PM exposure. Furthermore, circulating EPC responses to PM exposure, as well as the responsible mechanistic pathways, may differ between acute and chronic exposures. Indeed, long-term air pollution exposure has been associated with lower levels of EPCs, as a result of cumulative damage to the bone marrow or circulating EPCs, impaired EPCs’ release, and/or decrease of bioavailable EPCs because of their continuous mobilization and subsequent exhaustion. On the contrary, short-term exposure to high doses of PM more likely seems to resemble the biological responses associated with acute EPC levels increase (as myocardial ischemia, exercise, etc.), reflecting the natural mobilization of these cells for endothelial damage repair after PM exposure (Brook et al., 2013). Despite the link between air pollution and EPCs’ dysfunctions is clearly established, the mechanisms whereby different exposure times (long/short-term) could have opposite effects on EPCs’ number and function remain to be fully elucidated. In addition, the possibility that different EPC subpopulations may be differentially affected by PM exposure should be further investigated.

In conclusion, the association between the long-term exposure to ambient fine particles and the risk of cardiovascular disease development implies the need to improve the air pollution abatement for CVD prevention. On the other hand, in addition to good habits (i.e., healthy nutrition, healthy sleeping, and exercise (Kampfrath et al., 2011; Lui et al., 2013; Souza et al., 2020)), new strategies of intervention and prevention are required to improve EPCs’ number and function in order to mitigate the adverse effects of polluted air on human health.