SNAI2/SLUG: a key regulator of endothelial-to-mesenchymal transition and vascular remodeling in cardiovascular diseases

Abstract

Snail family transcriptional repressor 2 (SNAI2), also known as SLUG, is a canonical driver of epithelial-mesenchymal transition (EMT). While its oncogenic roles are well-established, emerging evidence underscores its pivotal involvement in cardiovascular diseases (CVDs). This review systematically summarizes the multifaceted functions of SNAI2 in the cardiovascular system, highlighting its role in mediating endothelial-to-mesenchymal transition (EndMT) and vascular smooth muscle cell (VSMC) phenotypic reprogramming. We detail the involvement of SNAI2 across a spectrum of pathologies, including atherosclerosis, aortic aneurysm, valvular heart disease, myocardial fibrosis, and pulmonary arterial hypertension. By acting as a critical nexus in signaling networks such as TGF-β, Notch, and Wnt, SNAI2 regulates cellular fate and extracellular matrix remodeling under pathological stress. Finally, we discuss the potential of SNAI2 as a diagnostic biomarker and a novel therapeutic target, offering prospective insights for the clinical management of CVDs.

Highlights

1. Snail family transcriptional repressor 2 (SNAI2) is a tumor promoting factor, while it has also been implicated in CVD development and prognosis.

2. SNAI2 is also highly associated with cardiac development and cardiovascular diseases, such as atherosclerosis, aortic aneurysm, heart valve disease, myocardial fibrosis, and pulmonary arterial hypertension.

3. Increased levels of SNAI2 contribute to multi-protein biomarker signatures for the diagnosis and prognosis of a broad plethora of CVDs.

Background

As a highly conserved protein-coding gene in vertebrates, Snail family transcriptional repressor 2 (SNAI2) encodes for the SLUG protein, which constitutes one of the three principal zinc finger transcription factors within the Snail family [1]. Initial research in the 1990 s identified SNAI2 as a critical inducer of epithelial-mesenchymal transition (EMT), facilitating mesoderm formation during gastrulation and the migration of neural crest cells from the neural tube in avian models [2]. In subsequent years, extensive research has firmly established SNAI2’s role as a canonical EMT-inducing transcription factor (EMT-TF), so that SNAI2 has been recognized as a master regulator of cellular plasticity across diverse physiological and pathological contexts [3]. In fact, its functions have now greatly exceeded our past understanding.

As the mechanistic backbone of this review, it is essential to define the cellular transformations orchestrated by SNAI2. EMT is a fundamental process where epithelial cells lose their specialized junctions and apical-basal polarity to acquire a migratory, mesenchymal phenotype. A closely related mechanism, endothelial-to-mesenchymal transition (EndMT), involves endothelial cells adopting mesenchymal characteristics, including enhanced motility and contractile properties [9–12]. Beyond these transitions, the vascular wall exhibits significant plasticity through the phenotypic transformation of vascular smooth muscle cells (VSMCs). VSMCs can shift from a mature, contractile state to a synthetic or mesenchymal-like phenotype, a process central to vascular remodeling and disease progression.

The position of SNAI2 in tumor formation and development is clear. In past studies, SNAI2-induced EMT led to a transformation of mature epithelial cells into mesenchymal cells with multidirectional differentiation potential, which participates in tissue development and repair, and causes an increased migratory capacity and promoting tumor growth and metastasis in cancer [4, 5].

In recent years, increasing evidence suggests that SNAI2 plays an important role in cardiovascular diseases (CVD). SNAI2 is mainly involved in CVD pathogenesis by inducing EndMT and EMT-like processes [6]. Although some of the diseases and their underlying causative mechanisms related to SNAI2 have been mentioned in the reviews by Zhou W et al. [7] and Cobaleda C et al. [1], as more and more functions of SNAI2 have been unearthed, Recent studies indicate that SNAI2-mediated cellular transformations contribute to a wide array of conditions, including atherosclerotic cardiovascular disease (ASCVD), aortic aneurysm (AA), heart valve disease, myocardial fibrosis (MF), and pulmonary arterial hypertension (PAH).

Current literature has established the importance of SNAI2 in specific pathological states. However, as the multifaceted functions of SNAI2 continue to be uncovered, a comprehensive synthesis of its roles across the cardiovascular spectrum is warranted. Therefore, this review focuses on summarizing the novel functions of SNAI2 in CVD, building a holistic framework of its molecular network, and intending to provide new ideas for CVD research prospectively with the breakthroughs of SNAI2 in cancers.

SNAI2 in cardiac development

The SNAI2 transcript is 2.2 kb in the placenta and adult heart, pancreas, liver, kidney, and skeletal muscle [8]. SNAI2 has been shown to regulate the function and differentiation of adult stem cells and progenitor cells in cardiovascular, skeletal, mammary, nervous system, epidermal, and mesenchymal tissues by inducing EMT or EndMT [9–12].

EMT is necessary for cardiac development. The EMT process occurs in the endothelial lining of the heart, known as the endocardium, leading to the formation of heart valve progenitor cells. In the early stages of heart development, there is an endocardial layer and a surrounding myocardial layer, which are separated by an extracellular matrix called cardiac jelly [13, 14]. During embryonic heart development, cellular transitions such as EndMT in the endocardial cushions and EMT in the epicardium are indispensable for forming heart valves and epicardium-derived cell lineages [15]. The ablation of genes expressed in the epicardium disrupts the growth of myocardial tissue, the development of coronary arteries, and the formation of cardiac interstitial cells [16, 17]. SNAI2 has been identified as a critical transcriptional regulator orchestrating these developmental programs.

Specifically, SNAI2 is expressed in the endothelial cells of the atrioventricular (AV) canal as well as in the mesenchymal cells found within the endocardial cushion. Treatment with antisense SNAI2 oligodeoxynucleotide on chicken AV canal explants inhibited the segregation of endothelial cells, indicating that SNAI2 may play a role in the early stage of EMT [18]. Jiang R et al. [19] found that mice deficient for SNAI2 are viable but are growth retarded and display defects in pigmentation and hematopoiesis. Niessen K and others [20] found that SNAI2−/− AV canal explants had significantly reduced migration and invasion compared with SNAI2+/− or wild-type controls at E9.5, but was restored by increased SNAIL expression at E10.5, illustrating the incomplete overlap of periods in which SNAIL and SNAI2 play a role in the EMT process. Second, SNAI2 is necessary for the generation of epicardium-derived cardiac fibroblasts, coronary vascular smooth muscle cells (cVSMCs), and peripheral cells. In conclusion, SNAI2 knockout models exhibit markedly reduced cell migration and invasion in AV canal explants, a defect that highlights the specific temporal requirements for SNAI2, that is distinct from other Snail family members such as SNAIL (SNAI1).

Furthermore, Jackson-Weaver O et al. [21] found that activation of the p53-SNAI2 pathway at E12.5 inhibits epicardial EMT and invasion, which ultimately impairs the formation of epicardial-derived cardiac fibroblasts, cVSMCs, and pericytes, thereby impairing coronary artery development and ventricular morphogenesis. Moreover, SNAI2 is essential for the adult epicardial EMT, a fetal genetic program, to support neovascularization and cardiac healing after myocardial infarction (MI) [22, 23].

Upstream signaling networks of SNAI2

SNAI2 serves as a critical signaling nexus, which integrate diverse upstream pathways to orchestrate EndMT and VSMC reprogramming. In the cardiovascular context, the canonical transforming growth factor-beta (TGF-β) pathway is the most prominent inducer of SNAI2. TGF-β signaling activates the YAP1/SMAD2/3/4 axis, which directly transcribes SNAI2 to initiate cellular phenotypic transitions [64]. Concurrently, the NOTCH signaling pathway critically regulates EndMT and endothelial survival via SNAI2 [91]. Notably, these pathways do not operate in isolation; NOTCH can independently activate SNAI2 and synergize with TGF-β-mediated EndMT progression through mediators like Sox9 [92]. Furthermore, Wnt signaling activation has also been shown to upregulate SNAI2, driving myocardial differentiation and EMT-like processes [120]. Importantly, SNAI2 creates a positive feedback loop by regulating extracellular matrix (ECM) remodeling, [113, 114] which in turn alters the mechanical stress and biochemical microenvironment of the vessel wall, thereby sustaining the activation of these upstream profibrotic pathways.

As we have discussed above, a critical nuance in cardiovascular pathogenesis is distinguishing the role of SNAI2 from its closely related family member, SNAI1. While SNAI1 and SNAI2 share structural similarities and canonical functions in tumor-associated EMT, their spatiotemporal expression patterns and regulatory specificities diverge significantly in CVDs. Current evidence suggests that SNAI2 is often subject to highly specific upstream regulation. For instance, in the context of myocardial fibrosis, the Brahma-related gene 1 (BRG1) synergizes with SP1 to specifically activate the SNAI2 promoter—without inducing SNAI1 or ZEB [84]. Similarly, in pulmonary arterial hypertension (PAH) models, the deletion of BMPR2 combined with HMGA1 upregulation exclusively induces SNAI2, rather than SNAI1, to drive a distinct EndMT process [104].

Furthermore, their temporal dynamics differ markedly during disease progression. In monocrotaline-induced PAH, NOTCH-mediated SNAI2 upregulation occurs later but persists for a significantly more extended period compared to the transient spike of SNAI1 [101]. This indicates that while SNAI1 may be involved in the acute, initial response to vascular injury, SNAI2 acts as the primary driver for sustained, chronic pathological vascular remodeling. Recognizing these context-dependent and temporally distinct roles is paramount, as it highlights why selectively targeting SNAI2—rather than pan-Snail inhibition—holds unique translational potential for treating chronic CVDs.

SNAI2 in cardiovascular diseases

CVD remains the leading cause of morbidity and mortality globally, of which the annual deaths continue to rise [24]. In recent years, with the development of epigenetics and molecular cardiology, more and more pathogenic genes and molecular pathways have been uncovered, and some relevant markers can be significantly changed at the early stage [25, 26]. Current literature establishes that SNAI2 regulates the fate of various cardiovascular cells between physiological and pathological states in cardiovascular dysfunction [29–114]. (Fig. 1). Therefore, it is crucial to demonstrate the novel function of SNAI2 in CVD.

Fig. 1.

SNAI2 in cardiovascular diseases. In the diseased heart and vascular wall, the activation of SNAI2 actively induces EndMT, switches the VSMC phenotype, and remodels normal ECM architecture

Atherosclerotic cardiovascular disease

ASCVD, characterized by systemic vascular wall inflammation, remains the leading cause of death worldwide, including ischemic heart disease and ischemic stroke [27, 28]. Although some traditional single-gene studies of ASCVD have been conducted, a further understanding of the underlying pathobiology is required.

Regarding pathogenesis, vascular chronic inflammation and endothelial barrier dysfunction due to EndMT contribute to the development of AS and are widely observed in AS patients and animal models. Meanwhile, a similarly upregulated expression of SNAI2, an important EndMT-activating transcription factor, has been detected [29, 30]. In AS, exposure of EC to TGFβ produced by the vascular wall induces SNAI2 expression and EndMT, which ultimately exerts proinflammatory effects and increases vascular permeability [31, 32]. Garcia J et al. [33] demonstrated that EndMT induced by the MAPK pathway was SNAI2-dependent, reduced intercellular adhesion, promoted migration of endothelial cells, and disrupted the barrier. Zhang W et al. [34], using Bleomycin for treating vascular sclerosis, reported that Bleomycin activated SNAI2 via the Akt pathway, which prompted the transformation of human umbilical vein endothelial cells to fibroblasts, causing remodeling of the vascular wall.

VSMCs are a significant component of plaques and are involved in various processes throughout all stages of atherosclerosis (AS) with phenotypic transformation [35], and SNAI2 has been shown to be expressed in human carotid atherosclerotic lesions by VSMCs displaying a synthetic phenotype [36]. Xiao J et al. [37] showed that specific knockdown of TFPI-1 in VSMCs could cause upregulation of SNAI2 expression via the AMOT/YAP signaling pathway and promote the transformation to a synthetic phenotype, which enhanced the proliferation and migration of VSMCs. Another study showed that RGMa promotes the transformation of VSMCs to a macrophage-like phenotype by enhancing the action of SNAI2 via the MEK1/2 signaling pathway to promote the progression of atherosclerosis and intimal remodeling after injury [38]. A recent study has demonstrated that defects in the body’s antioxidant defense system upregulate the expression of SNAI2, which activates EMT to cause an acute increase in ROS, leading to oxidative damage [39]. Decreased BH4 and NO synthesis by eNOS uncoupling under oxidative stress inhibits HIF-1a, SNAIL1, SNAI2, and ALDH1A2 expression and the epicardial EMT process, which leads to congenital coronary artery malformations [40].

Vascular calcification and mechanical stress have definite effects on vascular function and atherosclerosis through the SNAI2 pathway [41, 42]. SNAI2 is preferentially expressed at sites of low shear stress predisposing to AS and promotes early atherogenesis by inducing EndMT in ECs and enhancing vascular permeability [43]. Moreover, SNAI2 could promote ECs lacking primary cilia to undergo a BMP-dependent osteogenic differentiation, which ultimately causes vascular calcification, and the trend of SNAI2 expression is consistent with the degree of vascular calcification [44, 45]. In the advanced stage, miR-466i-5p could cause an increase in SNAI2 expression via the PI3K-Akt signaling pathway, affecting cardiac remodeling that occurs after MI, while lncRNA Mirt1 could act as a ceRNA for miR-466i-5p to inhibit this effect [46].

Among the risk factors for ASCVD, smoking, hypertension, family history of premature ASCVD, primary severe hypercholesterolemia, and diabetes are all associated with SNAI2. Nicotine treatment can induce EndMT in ECs, causing cytoskeletal reorganization and barrier dysfunction, resulting in larger atherosclerotic plaques in ApoE-/- mice [47]. SNAI2 is an essential epigenetic regulator of adipogenesis, and its aberrant expression can lead to nonalcoholic fatty liver disease and type 2 diabetes [48]. Accumulation of oxidized LDL in the arterial wall can induce transdifferentiation of VSMCs and increase the fragility of plaques by upregulating SNAI2 expression [38]. Meanwhile, intracellular hyperglycemia induces excessive ROS production, which accelerates the development of AS by enhancing oxidative stress [49, 50]. Moreover, reduced SNAI2 expression during pregestational diabetes impairs epicardial EMT and induces coronary artery malformations in offspring [51].

In terms of treatment, coronary artery bypass graft (CABG) surgery remains the gold-standard treatment in many patients with complex multivessel coronary artery disease or left main disease. Despite substantial improvement in patients’ prognosis undergoing CABG surgery over the past decade, poor graft patency remains a shortcoming of the procedure [52]. Studies have shown that SNAI2 plays a vital role in the pathological remodeling and neointimal formation of human vein grafts and that blockade of TGFβ/Smad2/3-SNAI2 signaling pathway prevents restenosis of vein grafts [53]; furthermore, the saphenous veins, which are commonly used as conduits for CABG, is considered to have higher long-term patency when compared to the internal thoracic artery, which is considered to have a lower long-term patency, a lower degree of arterialization, and increased SNAI2 expression [54].

Aortic aneurysm

AA is the second most common aortic disease after atherosclerosis and the ninth leading cause of death worldwide [55]. Most AAs are nonspecific, and only a few aneurysms have a clear etiology secondary to other diseases such as atherosclerotic disease, trauma, connective tissue disease (Marfan Syndrome, Ehlers-Danlos Type IV), infectious disease (tuberculosis, syphilis, bacteria, fungi), and inflammatory diseases [56]. The pathogenesis is currently thought to include dysfunction of the endothelium, loss of the extracellular matrix (ECM), medial degeneration, and low-grade aortic wall inflammation, with loss of medial VSMCs and phenotypic transformation being essential features of AA [57].

SNAI2 may be a crucial link between EndMT and the endothelial dysfunction observed in AA. Utilizing a murine model of aortic aneurysm (AA) generated via periadventitial elastase application in CDH5-Cre lineage tracing mice, Millar JK and colleagues demonstrated that SNAI2 upregulation exacerbates aortic dilation through the induction of Endothelial-to-Mesenchymal Transition (EndMT) [58]. The correlation between SNAI2 and phenotypic transformation in AS has been mentioned as mentioned earlier, and VSMCs from Marfan Syndrome mice induced by FN1 mutations also showed markedly elevated SNAI2, suggesting a mesenchymal-like phenotypic transformation, which leads to impaired force-generating capacity and aortic dilatation [59]. A recent study presented that a sizable number of contractile VSMCs in the aortic media of AA patients are reprogrammed to an MSC-like intermediate state, which induces aortic growth exuberance and dilatation, calcification and ossification of the aortic wall, as well as inflammation [60]. This reprogramming is hugely similar to the SNAI2-mediated EMT/EndMT process, but further studies are needed to find a direct correlation between SNAI2 and this reprogramming process. More strikingly, in patients with Infantile hemangiomas, significant perivascular infiltration of M1 macrophages was consistent with SNAI2. Mechanistically, M1 macrophages induced EndMT to promote infantile hemangioma regression by upregulating SNAI2 expression, providing a novel therapeutic direction [61].

Heart valve disease

More than 40 million people worldwide suffer from valvular disease, and the trend continues to increase [62]. EndMT is a necessary step in valve development, of which SNAI2 is a vital regulator [63]. In ECs of the endocardial cushions, TGFβ can activate the expression of SNAIL, TWIST, and SNAI2 via the YAP1/SMAD2/3/4 signaling axis, which in turn affects the formation and development of end-form valves [64]. In actual cases, EndMT and SNAI2 expressions were more pronounced in bileaflet aortic valve-derived ECs [65]. Moreover, aberrant expression of SNAI2 will cause severe congenital phenotypic abnormalities in heart valves and septum [66].

Disturbances in the interactions between valve endothelial cells and valve interstitial cells are considered one of the pathogenetic mechanisms of adult heart valve disease [67]. Valve endothelial cells play an important role in the valve’s dynamic homeostasis and adaptive response, while interstitial cells, as the primary producers of ECM, play a key role in maintaining the structural and functional integrity of the leaflets [68]. Recent studies have found that EndMT increases in mitral leaflets exposed to mechanical distraction and undergoes osteogenic differentiation, causing compensatory increases in mitral leaflet thickness and area, and interstitial cells can inhibit this process [69, 70]. In addition, Gao L et al. [71] found that overexpression of SNAI2 in porcine aortic valve interstitial cells increased the expression of the osteogenic marker RUNX2, and SNAI2 knockdown attenuated interstitial cells calcification and p53-mediated calcium deposition as well as the expression of osteogenic markers. Thus, inhibition of EndMT is expected to be a therapeutic target for heart valve disease.

Myocardial fibrosis

MF is a series of quantitative and qualitative changes in the collagen network of the interstitial myocardium resulting in cardiac structural remodeling and dysfunction in response to ischemic injury, systemic disease, drugs, or any other deleterious stimuli affecting the circulatory system or the heart itself [72, 73]. MF is a process conducive to the development of a variety of CVDs, closely linked to cardiac arrhythmia, cardiac dysfunction, and even sudden cardiac death. Moreover, MF is considered an independent risk factor for the incidence and mortality of CVDs [74]. In other words, MF is an important target for the prevention of terminal events in CVDs. The central event in MF is the abnormally enhanced synthesis and secretion of extracellular matrix proteins by activated fibroblasts and myofibroblasts, which causes diffuse and disproportionate collagen aggregation in the myocardial interstitium [75]. EndMT is the initiating event in MF and has been identified as a target for the treatment of fibrotic diseases. In the past, the SNAIL-induced EndMT was thought to be the main source of activated fibroblasts [76], whereas SNAI2 has gradually been found to show the same effect.

Diabetes and hypertension are common causes of myocardial fibrosis, and a common feature of MF in diabetes and hypertension is the dysregulation of the renin-angiotensin-aldosterone system (RAAS) [77–79]. AngII can promote the EndMT process and thus cause a reduction of endothelial markers such as CD31 and vWF and an increase of fibroblast-specific markers vimentin, fibroblast-specific protein-1, α-SMA by upregulating SNAI1, SNAI2, TWIST, and ZEB [80–83]. In particular, Brahmarelated gene 1 synergizes with the SP1 binding with the SNAI2 promoter region to activate SNAI2 specifically but not SNAI1 and ZEB transcription, which functions as a repressor of endothelial gene CDH5 transcription and promotes EndMT [84]. Conversely, vascular endothelial ETS-1 specific knockdown inhibits SNAI1, SNAI2, TWIST, and ZEB1 expression, which inhibits the AngII-induced EndMT and reduces myocardial fibrosis and hypertrophy [85].

The TGFβ signaling pathway is another important mechanism that promotes EndMT. After being subjected to mechanical strain such as cyclic stretch, ECs upregulate the expression of SNAI2 via the TGFβ pathway and promote EndMT to adapt to the altered environment, whereas TGFβ at pathological concentrations causes organ fibrosis [86, 87]. MiR-155 positively regulates TGF-β-induced cardiac fibrosis via c-Ski, while MFGE8 exerted a protective effect by inhibiting the phosphorylation of smad2/3 and accumulation of heteromeric complexes in the nucleus, which reduces the expression of SNAIL, TWIST, and SNAI2 [88, 89]. Ursolic acid from the Bushen Yijing Formula also inhibited HUVEC EndMT and fibrosis by suppressing SNAI2, SNAIL, and TWIST gene expression [90]. In addition, SNAI2 is required for survival in NOTCH-activated ECs [91]. SNAI2 can be directly activated by the NOTCH signaling pathway independently of TGFβ and SNAIL and synergistically induces TGFβ-mediated EndMT progression by Sox9 protein [92]. Surprisingly, GHMT could inhibit TGFβ-mediated profibrotic signaling by downregulation of SNAI2 and SNAIL to induce fibroblast reprogramming into cardiomyocytes [93]. Several other studies have shown that TGFβ pathways regulate the process of myocardial fibrosis with a lack of downstream EndMT transcription factors. Therefore, it is valuable to investigate SNAI2 as a potential effector molecule [94–96].

Pulmonary arterial hypertension

PAH is a group of disorders characterized by abnormally high pressures in the pulmonary arteries [97]. According to the statistics, it is a category of CVDs that poses a severe threat to human health and affects at least 1% of the world’s population, with the burden being greater in low-income and middle-income countries [98]. The pathology of PAH is characterized by the induction of neovascularization, intimal hyperplasia, vasoconstriction, and thrombosis due to the abnormal proliferation of pulmonary vascular cells (mainly ECs and SMCs), which ultimately causes luminal narrowing of small pulmonary arteries and generates high pulmonary circulatory resistance [99]. SNAI2 expression was significantly upregulated in human pulmonary arteries with a high degree of vascular remodeling and in PAH-related vascular remodeling mouse models, and SNAI2 expression was positively correlated with the degree of pulmonary obstruction and arterial wall thickness [100, 101].

SNAI2 is involved in PAH pathogenesis in two main ways. The first is the induction of EndMT in pulmonary artery ECs, which causes endothelial dysfunction, which has been the focus of most articles in recent years. Gonzales et al. used Hemin treatment of pulmonary artery ECs to mimic PAH in sickle cell disease and revealed that Hemin exposure caused upregulation of SNAI1 and SNAI2 expression, promoting EndMT and ultimately leading to uncontrolled cell proliferation [102]. Otsuki et al. indicated that in PAH, monocytes or macrophages can release HERV-K dUTPase in the form of extracellular vesicles, which induces increased expression of SNAI1 and SNAI2 in ECs via TLR4/p38/NF-κB signaling and TLR4/JNK/SMAD3 signaling pathways, which promotes EndMT and increases the expression of VCAM1 [103]. Patients with BMPR2 mutations are genetically susceptible to PAH. Deletion of BMPR2 in PAECs synergized with upregulation of HMGA1 only induced the expression of SNAI2 instead of other transcription factors such as SNAI1, inducing an EndMT process different from that mediated by TGFβ, and this effect could be entirely counteracted by knockdown of SNAI2 mRNA [104]. Nikitopoulou I et al., using monocrotaline to establish PAH rats, also found the fact that increased SNAI2 expression is the result of NOTCH activity appearing later but acting for a more extended period compared to SNAI1 [101]. Baicalein could inhibit SNAI2 expression by suppressing NF-κB signaling and thus attenuating MCT-induced PAH in rats [105]. More surprisingly, in pulmonary arterial hypertension (PAH), CD44v—a recognized cell-surface marker for cancer stem cells (CSCs) undergoing EMT—is co-expressed with SNAI2 on EndMT-like cells within the pathological neointima of pulmonary arterioles. The concordant expression patterns of CD44v and SNAI2 observed in vitro support the hypothesis that CD44v emergence may be a consequential outcome of SNAI2-driven EndMT. [106, 107], CD44v+cells showed the highest expression levels of proinflammatory cytokines, antioxidant enzymes, antiapoptotic molecules, and cyclin-dependent kinase inhibitors [108], accelerating the development of PAH.

Bone marrow-derived endothelial progenitor cells (EPCs) can be mobilized into the circulatory system after endothelial injury in pulmonary arteries [109], and Díez M and other investigators found that when circular EPCs were co-cultured with mature SMCs or placed in the lumen of transplanted pulmonary arteries, the expression of SNAI2 would be markedly increased, which induced the differentiation of EPCs into cells expressing α-SMA [110]. In the hypoxic environment induced by PAH, the expression of HIF-2ɑ increases in pulmonary artery ECs, which in turn causes an increase in the expression of SNAI1 and SNAI2, exacerbating PAH through the promotion of EndMT formation in a positive feedback effect [111]; on the contrary, BMP-7 can inhibit hypoxia-induced EndMT and PAH via mTORC1 signaling [112].

In addition to inducing EndMT, SNAI2 has a unique mechanism involved in the pathogenesis of PAH. Previous studies have shown that SNAI2 regulated extracellular matrix remodeling [113]. Ruffenach G et al. found that SNAI2 expression was upregulated 2.5-fold in macrophages from lung tissue of patients with pulmonary hypertension secondary to pulmonary fibrosis (PF-PH) compared to PF alone, and that increased SNAI2 expression directly caused increased secretion of extracellular matrix protein-prolactin-induced protein and induced ECs and SMCs proliferation [114]. In conclusion, SNAI2 is strongly correlated with PAH pathogenesis, and targeting SNAI2 may bring breakthroughs in the treatment of PAH.

Other cardiovascular diseases

Osoegawa K and other investigators showed an increased risk of conotruncal heart defects in infants with homozygous deletion of SNAI2 [115]. In fact, SNAI2-mediated EndMT in the atrioventricular canal and the ventricular outflow tract is critical for cardiac development [116]. Pérez-Mancera PA have linked SNAI2 genetic duplications with severe congenital defects such as tetralogy of Fallot. Complementary transgenic models reveal that adult mice overexpressing SNAI2 exhibit an increased incidence of sudden death, cardiomegaly, and cardiac failure [117]. High salt exposure inhibits basement membrane breakdown by affecting RhoA, which interferes with SNAI2/E-cadherin/N-cadherin/Laminin expression and leads to interference with EMT and mesoderm formation and malformation of heart tubes [118]. The expression of SNAI2 in atrial fibrillation patients was significantly higher, and the upregulated expression was enriched in the functional regions of “regulation of calcium release into the cytosol,” “actin cytoskeleton organization,” and “adhesion plaque.” However, the exact mechanisms need to be further investigated [119]. In addition, SNAI2 is involved in myocardial differentiation induced by Wnt signaling. The use of Wnt activators triggered rapid and extensive apoptosis in induced pluripotent stem cells (iPSCs), as evidenced by cleaved caspase 3, PARP cleavage, and annexin exposure, which promoted the increased expression of SNAI1, SNAI2, and EMT, and induced pluripotent differentiation of iPSCs [120]. The whole functions of SNAI2/SNAI2 in CVDs are summarized in Table 1.

Table 1.

The functions of SNAI2/SLUG in CVDs

Associated disorder	Functions	Human /animal	References
Atherosclerotic cardiovascular disease	Serves as a biomarker for TGFβ-induced EndMT Contributes to enhanced vessel wall inflammation by inducing EndMT	Human	[29, 30]
	Significantly elevated under low shear stress Contributes to endothelial dysfunction and enhanced vascular permeability by inducing EndMT	Human and animal	[41, 43]
	Significantly elevated in human and mouse carotid atherosclerotic lesions. Contributes to atherosclerotic plaque progression by inducing VSMC phenotypic transformation	Human and animal	[36–38]
	Positive correlation with vascular calcification degree Contributes to vascular calcification	Human and animal	[44, 45]
	Contributes to cardiac remodeling	Animal	[46]
	Contributes to neointimal formation in interpositional vein grafts	Human and animal	[52]
Aortic aneurysm	Significantly elevated in aortic neurysms Contributes to endothelial dysfunction by inducing EndMT	Human and animal	[58, 61]
	Contributes to inflammation and calcification of the aortic wall by inducing VSMC phenotypic transformation.	Animal	[59, 60]
Heart valve disease	Contributes to atrioventricular valve development	Animal	[64]
	Contributes to valvular hyperplasia and adaptive responses after myocardial infarction by inducing EndMT.	Human and animal	[66–69]
	Significantly elevated in heart valve disease patients Contributes to valvar calcification	Human and animal	[65, 70, 71]
Myocardial fibrosis	Serves as a biomarker for myocardial fibrosis Contributes to induction of ECs transformation into fibroblasts by EndMT	Human and animal	[80, 82–90, 92]
	Contributes to reprogramming of fibroblasts into cardiomyocytes	Human and animal	[93]
	Contributes to survival in NOTCH-activated ECs	Human	[91]
Pulmonary arterial hypertension	Serves as a biomarker for EndMT Contributes to enhanced oxidative stress, inflammation and endothelial dysfunction by inducing EndMT	Human and animal	[101–104, 111, 112]
	Significantly elevated in highly remodeled human and mouse pulmonary arteries. Contributes to vascular remodeling by inducing VSMC phenotypic transformation	Human	[100]
	Contributes to intimal hyperplasia by inducing EndMT in EPCs	Human	[110]
	Contributes to acquisition of stem-like features	Human and animal	[108]
	Contributes to ECM remodeling	Human and animal	[114]
Atrial fibrillation	Significantly elevated in atrial fibrillation patients	Human	[119]
Congenital heart defects	Serves as a biomarker for epicardial EMT Contributes to coronary artery development and coronary artery anomalies	Animal	[40, 51]
	Significantly associated with conotruncal defects among boys	Human	[115]
	Contributes to cardiac cushion morphogenesis by inducing EndMT	Human and animal	[116–118]
	Contributes to pluripotent differentiation of iPSCs	Human	[120]

In conclusion, all the above studies indicate that both the congenital defect and acquired pathological regulation of SNAI2 are related to the development of various CVDs and that the treatment targeting SNAI2 has achieved better results in some studies, suggesting that SNAI2 has a superior scientific value and clinical prospects.

Therapeutic potential and challenges

The involvement of SNAI2 in diverse cardiovascular pathologies shows its potential as a novel therapeutic target. Current interventions could transition from systemic approaches to precision medicine by targeting SNAI2-driven EndMT and VSMC phenotypic switching. Specifically, RNA-based therapies offer a promising avenue to selectively silence SNAI2 in diseased vascular tissues. Furthermore, high-throughput screening for small-molecule inhibitors that disrupt SNAI2’s transcriptional activity or its interaction with co-activators like SMADs remains a high-priority research direction [121].

Moving these strategies into the clinic presents distinct challenges. SNAI2 plays a highly complex role in cellular homeostasis. While inhibiting it helps prevent pathological remodeling in the heart, the body still requires SNAI2 to maintain adult stem cells and promote standard tissue repair. Without it, stem cells in the mammary epithelium age prematurely, and Schwann cells fail to adapt during nerve regeneration. Because of this dual function, widespread systemic inhibition could trigger severe side effects, such as impaired wound healing or broader tissue degeneration. To bypass these risks, future therapeutic development must focus on strictly localized delivery systems. Using tools like ligand-functionalized nanoparticles or drug-eluting stents can ensure that SNAI2 inhibitors reach only the targeted cardiovascular tissues, thereby protecting healthy cells elsewhere.

Conclusion

Since the initial discovery of the role of SNAI2 in EMT, it has become clear that this transcription factor plays a multifaceted role in crucial biological processes essential for tissue homeostasis. For years, the scientific community viewed SNAI2 almost exclusively through the lens of oncology. The evidence we reviewed here makes a clear shift in that perspective. SNAI2 actively drives cardiovascular pathogenesis. It acts as a fascinating molecular bridge. By initiating EndMT, reprogramming VSMCs, and altering the extracellular matrix, diseased blood vessels essentially co-opt the cellular playbook of cancer metastasis. This realization makes SNAI2 much more than a passive diagnostic footprint. It is a direct and viable target for intervention.

We must, however, approach this new therapeutic frontier with strict caution. As discussed, the risk of disrupting normal tissue regeneration is a genuine concern. Achieving absolute tissue specificity is not merely a clinical preference—it is a mandatory requirement to avoid off-target damage. Modulating the SNAI2 signaling axis effectively will depend entirely on our ability to navigate this delicate biological balance.

Author contributions

JunXu, Qingchen Wu and Cheng Zhang: Conceptualization, Supervision. Tong Yang : Writing - Original Draft. Zihao Liu and Haoyu Ran : Writing - Review & Editing. All authors read, reviewed, and approved the final manuscript.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

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Competing interests

The authors declare no competing interests.