Depending on the region of the aorta involved in the aneurysm, it can be categorized as a thoracic aortic aneurysm (TAA) or abdominal aortic aneurysm (AAA) (Davis, Daugherty, & Lu, 2019; Shen, LeMaire, et al., 2020). Although TAA and AAA share some standard features (Guo, Papke, He, & Milewicz, 2006), such as similar anatomical appearance, absence of smooth muscle cells, and alterations in the extracellular matrix, they are distinct disorders with different population prevalence and modes of inheritance (Bossone & Eagle, 2021), which may be a consequence of their specific embryonic origins (Fig. 2). In distinction to the smooth muscle cells of the abdominal aorta, which originate only in the splanchnic mesoderm, the smooth muscle cells of the thoracic aorta originate in the neural crest and somatic mesoderm (Majesky, 2007). Aortic dissection is predisposed to the descending aorta, i.e., thoracic aortic dissection (TAD), probably since the thoracic aorta is differentiated from different layers during embryonic development (Gao et al., 2023; Ruddy, Jones, & Ikonomidis, 2013). There are various classification systems regarding aortic aneurysms. However, from a therapeutic medical point of view, they can be divided into two main categories: primary aortic aneurysms and secondary aortic aneurysms (Lindeman & Matsumura, 2019). Primary aortic aneurysms are associated with matrix defects in the vessel wall, and secondary aortic aneurysms are associated with extensive matrix turnover and pathological vessel wall remodeling in response to primary diseases. Like Marfan syndrome (MFS), Ehlers-Danlos syndrome is primary, whereas aneurysms triggered by infectious, immune, and degenerative diseases are secondary. The most common secondary aortic aneurysm is AAA, caused by vascular degeneration. Aortic aneurysms can be categorized into hereditary and sporadic depending on the etiology (Pinard, Jones, & Milewicz, 2019; Shen, LeMaire, et al., 2020). Approximately 20% of patients with TAA or TAD exhibit an autosomal dominant pattern of inheritance. A single gene mutation causes thoracic aortic disease while AAA does not usually show this inheritance. The causative gene for thoracic aortic disease typically does not increase the risk genes for AAA.

Genetics is a critical distinction between TAA/TAD and AAA. TAA/TAD is mostly autosomal dominantly inherited with a single gene causing the disease (Pinard et al., 2019). AAA is mainly associated with environmental factors (Golledge, Thanigaimani, Powell, & Tsao, 2023). Studies have shown that the complex genetic background of TAA/TAD is associated with connective tissue disorders, including MFS due to FBN1, Ehlers-Danlos syndrome due to mutations in type III collagen (COL3A1), Loeys-Dietz syndrome due to mutations in transcription growth factor-β (TGFB) or actin, and v-SKI avian sarcoma (SKI) (Takeda & Komuro, 2019). These are collectively referred to as syndromic TAA/TAD, and are characterized by early age of onset, rapid progression, and high criticality. In comparison, non-syndromic TAA/TAD occurs in middle-aged and older adults and is mainly sporadic. Although non-syndromic TAA/TAD is currently under-recognized and under-diagnosed. However, a clinical study found that among the 226 cases of non-syndromic TAA/TAD, the percentage of nonfamilial patients is 31.4%, and the detection rate of their mutations could be as high as 26.8%(Arnaud et al., 2019). So far, genetic research progress has confirmed that at least 37 genes may be associated with TAA/TAD (Faggion Vinholo et al., 2019). These results reveal four primary pathogenic mechanisms of TAA/TAD including altering extracellular matrix proteins (pathogenic variants in FBN1, FBN2, LOX, BGN, MFAP5), altering TGFB signaling proteins (TGFB2, TGFB3, TGFBR1, TGFBR2, SMAD2, SMAD3, SMAD4), altering smooth muscle cell (SMC) contractile function (ACTA2, MYH11, MYLK, PRKG1, MAT2 A, FLNA, LMOD1), and impairing SMC differentiation and proliferation (FOXE3) (Ostberg, Zafar, Ziganshin, & Elefteriades, 2020). The significant risk factors for thoracic aortic disease are high blood pressure and underlying genetic alteration (Pinard et al., 2019). A high-risk causative gene for thoracic aortic disease has been identified as a heritable risk for thoracic aortic disease (HTAD). HTAD is essential for identifying individuals at increased risk for thoracic aortic disease (Renard et al., 2018).

AAA is a multifactorial disease with genetic and environmental factors associated with its development (Golledge et al., 2023). Smoking, advanced age, positive family history, and being male increase the risk of developing AAA. In that these risk factors are equally occlusive atherothrombotic disease risk factors, AAA is often thought to be associated with atherosclerosis(Guo et al., 2006; Kasashima et al., 2018). Meanwhile partial evidence from molecular studies suggests that atherosclerosis and AAA are distinct disease entities(Golledge, 2019). The prevalence of AAA is lower in patients with diabetes than in the general population, whereas the prevalence is higher in patients with occlusive thrombophilia than in the general population (Golledge, Muller, Daugherty, & Norman, 2006; Lederle et al., 1997). The growth rate of AAA is also slower in diabetic patients (Dattani, Sayers, & Bown, 2018; Golledge et al., 2008; Sweeting, Thompson, Brown, Powell, & collaborators, R., 2012; Xiong, Wu, Chen, Wei, & Guo, 2016), which may be related to the application of metformin drugs in diabetic patients (Fujimura et al., 2016; Golledge et al., 2017; Itoga et al., 2019). Metformin has been reported to inhibit AAA development in animal models, but the certainty of evidence that metformin limits AAA growth in clinical studies is very low, making the four ongoing randomized trials key to clarifying whether metformin is effective in AAA (Golledge et al., 2021; Wang et al., 2019; Wanhainen, Unosson, Mani, Gottsater, & Investigators, 2021). A twin study shows that the heritability of AAA ranges from 70% to 77%(Joergensen et al., 2016). Individuals with a family history of AAA have a multifold increased risk of developing AAA (OR 3.80, 95% CI 3.66, 3.95) (Golledge et al., 2023; Summers, Kerut, Sheahan, & Sheahan 3rd., 2021). Thus, genetic mechanisms are closely related to the pathogenesis of AAA. Using genomic data may provide a means of personalized medicines in the future. This is important that personalized drug targets are established and may be more effective. Genome-wide association studies (GWAS) have identified a number of common single nucleotide polymorphisms (SNPs) that determine AAA risk (Golledge et al., 2023; Klarin et al., 2020). In addition, the presence of multiple non-coding RNA in AAA has been linked to the pathogenesis of AAA (Kumar, Boon, Maegdefessel, Dimmeler, & Jo, 2019).

At present, there are no effective drugs to prevent or treat aortic aneurysms, and treatment of aortic aneurysms relies on open or endovascular repair (Bossone & Eagle, 2021; Golledge et al., 2023). For example, in principle, asymptomatic small AAAs rely on repeat ultrasound imaging at 36-month intervals, whereas current guidelines for asymptomatic large AAAs, symptomatic AAAs, and ruptured AAAs recommend open or endovascular repair, thus great potential exists for finding drugs that can stop or slow the progression of aortic aneurysms, thereby alleviating or delaying the need for surgical repair. However, all existing models of aortic aneurysm disease are flawed, resulting in a discrepancy between successful preclinical experiments and failed clinical trials (Busch et al., 2021; Gao et al., 2023). It is crucial to find and establish novel animal models that better reflect human pathophysiology and identify biomarkers to predict the severity of aortic aneurysm progression. However, the curability of aortic aneurysms may result from a combination of complex genetic factors and multiple environmental factors. It may be difficult to stop its continued progression or eradicate it with a single drug therapy or surgical repair. The development of single-cell sequencing and multi-omics technologies has demonstrated complex interactions between cells in aortic aneurysms (Li et al., 2020; Yang, Zhou, Stranz, DeRoo, & Liu, 2021; Zhao et al., 2021). Single-drug targets may not be suitable to address this complex disease effectively. In China, natural products have been applied as a conventional treatment for cardiovascular diseases (Zhao et al., 2020) for more than 3000 years, and are also referred to as natural products.

In the current paper, we present an overview of the classification of aortic aneurysms, their embryonic origin, and genetic and environmental pathogenic mechanisms, and highlight the potential of natural products for the treatment of aortic aneurysms by reviewing the current scientific evidence for the application of natural products concerning the molecular mechanisms of aortic aneurysms. With the development of multi-omics, synthetic biology, and new computational technologies, natural products-based drug development for cardiovascular diseases holds promise for future aortic aneurysm disease treatments, and this paper aims to provide a theoretical basis for the development of novel natural products-derived drugs.