In the normal aortic media, the vasa vasorum is sparse, and nutrition relies on diffusion from the lumen [16]. However, reports from 30 years ago have suggested an increased number of vasa vasorum associated with aneurysmal dilatation [17, 18, 19]. According to a report, medial microvessel density (MVD) was approximately 15-fold higher in AAA than in normal aorta [20]. In addition, the number of neovessels in patients with AAA was approximately three times higher than that in the atherosclerotic control group [20, 21]. Another study found that the density of CD34-positive microvessels was higher in AAA than in aortic occlusive disease [22]. Moreover, MVD was higher in inflammatory AAA than in atherosclerotic AAA [22]. Ultimately, angiogenesis is widely recognized as a characteristic change in AAA.

In the normal human thoracic aorta, the vasa vasorum is located between the outer third of the media and adventitia [8]. In TAA, neovascularization was increased close to the adventitia and extended inward across one-third of the external media [8, 23]. MVD (marked by von Willebrand factor (vWF)) in the media gradually decreases from the exterior to the interior, and these neovessels never reach the intima of the thoracic AA/AD [8]. Compared with healthy aortas, MVD was significantly higher in monogenic mutant and degenerative forms related to TAA than in bicuspid aortic valve (BAV) forms [8]. However, according to Billaud M et al. [24], adventitia MVD was decreased in patients with aneurysmal TAV compared with that in those with non-aneurysmal TAV. The different conclusions of these studies may be because of the different calculation methods used for MVD. In Billaud M’s study [24], MVD was calculated by dividing the total number of vessels observed on aortic cross-sections (hemotoxylin and eosin-stained) by the adventitial area. However, it is inaccurate to evaluate the neovessels by counting the number of blood vessels because the diameter of capillaries is usually ˂10 µm, thereby limiting distinguishing using light microscopy, and massive local infiltration of inflammatory cells may interfere with the counting.

In addition, previous studies have shown obvious thickening of the adventitial vasa vasorum in human thoracic AD [25, 26]. Vessel growth extended to the outer two-thirds and inner third of the media in 86% and 19% of thoracic AD samples, respectively [25]. Furthermore, vascular growth was observed in more than half of the samples at the edge of the thoracic AD [25]. Therefore, combined with experimental animal thoracic aortic samples, these results showed that angiogenesis occurs in abdominal aortic disease and thoracic AA/AD and that neovascularization penetrates the media originating from the adventitial vasa vasorum [23].

Animal models are an important way for researchers to explore disease mechanisms. Current animal models of AA/AD are primarily of rats and mice, and they are generally categorized into the following treatment categories: (1) extraluminal application of CaCl${}_2$ and elastase in the abdominal aorta to induce inflammation [27, 28]; (2) angiotensin-II (Ang II) subcutaneous infusion for ApoE${}^{-/-}$ mice to mimic atherosclerosis-caused aortic dilatation and lesions; and (3) intraluminal application of elastase for the abdominal aorta or oral beta-aminopromazine (BAPN) to induce destruction of elastic layers followed by chronic inflammation [28, 29].

Although these models can induce the expansion of the aortic wall or dissection, none of them can completely simulate human AA/AD lesion characteristics [30]. For example, the intraluminal rather than the extraluminal application of elastase-induced AAA is complicated by media angiogenesis, which is a common characteristic of AA/AD [28]. Furthermore, angiogenesis in the human AA/AD sample was more dominant than that in the animal AA/AD model [20]. This phenomenon may be explained by several reasons as follows: AA/AD in humans is usually caused by decades of damage to vessels, but animal models were induced in ˂1 month; application of CaCl${}_2$ induces AA and results in the absence of MMP2 and MMP9, but they are abundant in human AA and have a dramatic pro-angiogenic effect; and mural thrombosis is common in human AA/AD, and the thrombus-covered wall is hypoxic, particularly in the inner thirds of the media, but all of the above-accepted models are without an obvious mural thrombus [31]. Moreover, angiogenesis was observed in angiotensin II- [32, 33], CaCl${}_2$- [34], elastase- [35], and BAPN- [36] induced AAA models, which indirectly verified that angiogenesis in the media and adventitia is one of the pathological features of AAA. However, evidence of angiogenesis in abdominal or Stanford type B-AD is lacking to our knowledge. Furthermore, this phenomenon may be due to insufficient attention given to type B-AD in preclinical studies.

Angiogenesis is associated with AA/AD incidence and disease severity. For example, the upregulation of $\alpha$${}_{\text{v}}$mRNA and $\alpha$${}_{\text{v}}$$\beta$3 integrin in the blood vessels surrounded by a matrix-expressing tenascin suggests that angiogenesis is an ongoing process in mature AA [37]. Furthermore, Choke E et al. [22] reported that human medial neovascularization is increased in the rupture edge of AAA than in the non-ruptured aneurysm anterior sac. Similarly, MVD is enhanced in patients with ruptured AAA than in those with non-ruptured AAA [21]. Moreover, increased neovessel growth was observed at the edge of type A-AD [25]. These results have attracted more attention to the pathological role of angiogenesis in AA/AD.

Traditional concepts of vascular inflammation are considered ‘inside-out’ responses centered on the monocyte adhesion and lipid oxidation hypotheses [38, 39]. In AA/AD, the adventitia changes significantly during angiopathy progression and thickens with the expansion of the vascular wall [40]. Adventitial vasa vasorum neovascularization is associated with a marked increase in capillary permeability [41] and chemokine levels [42], which may enhance the migration of inflammatory cells to angiogenic sites. Therefore, adventitial cells become highly populated by macrophages, lymphocytes, and neutrophils (Fig. 1) [40]. Indeed, AAA pathogenesis initiates macrophage migration into the adventitia, followed by a subsequent presentation in the media [43]. Therefore, according to the “outside-in” hypothesis, vascular inflammation of AA/AD is initiated from the adventitia neovessel and progresses inward toward the intima [44]. This explains that the vascular pathology of AA/AD (outside-in), to some extent, involves stronger pathological changes, such as media degradation and angiogenesis, than that of atherosclerotic angiopathy (inside-out).

Numerous evidence has demonstrated that macrophages are involved in AA/AD by secreting pro-inflammatory factors, metalloproteinases, and other substances to induce VSMCs apoptosis, ECM degradation, and neovessel formation, leading to aortic wall destruction and weakening [45, 46]. Most macrophages that accumulate in the aneurysmal or dissected aortic wall originate from circulating monocytes, whereas only a few macrophages are derived from aortic tissue-resident macrophages.

Previous studies revealed a close spatial correlation between neovessels and inflammatory infiltration in the AAA wall, of which most cells were monocytes/macrophages and lymphocytes [20]. Moreover, neovascularization was positively correlated with the number of lymphocytes in AAA samples (CD31: r = 0.625; CD105: r = 0.692) [47]. The predominant lymphocyte cell infiltrates were shown as CD4${}^{+}$CD8${}^{+}$T cells and infiltrates of type 2 Th cells, and their production induces AAA [48]. Kokje VBC et al. [49] reported that neutrophils infiltrated extensively into AAA tissues and had positive staining (myeloperoxidase staining) in the proliferative vasa vasorum, whereas they were absent in atherosclerotic control samples. This result suggests that angiogenesis promotes neutrophil infiltration, which has been proven to induce the occurrence and development of AA/AD [50, 51, 52]. Furthermore, the number of microvessels identified by CD31 was markedly increased in the human and mouse AAA models, consistent with harmful platelet infiltration [53]. These results suggest that neovascularization in all arterial wall layers is prominent, and angiogenesis can facilitate chronic inflammation [20].

A previous study confirmed lymphangiogenesis in the AAA wall [47], and lymph stasis was observed using indocyanine green fluorescence lymphography. Additional results demonstrate that enhanced infiltration by angiogenesis and relatively insufficient lymph drainage are associated with an increased number of macrophages in AAA [54].

Excluding the infiltration of immune-inflammatory cells caused by poor mural cell coverage and defective endothelial junctions, Kessler K et al. [8] found that an incomplete endothelial structure was associated with plasminogen and albumin accumulation in the media of human aorta samples, leading to TAA remodeling and weakening. Moreover, tissue inhibitors of metalloproteinase and gelatinase (collagenase) are localized to the vasa vasorum of AA, which strongly suggests that angiogenesis possibly involves the genesis of AA/AD [18].

Numerous studies have confirmed that macrophages are the main inducers of aortic vascular inflammation and play a key role in AA/AD progression [45, 46]. In addition to their immunological and inflammatory functions, they promote angiogenesis by producing pro-angiogenic cytokines and growth factors, such as VEGF-A and basic FGF-2, in animal models [36]. Moreover, in patients with Stanford type A-AD, macrophages play a central role in aortic wall remodeling by inducing the release of MMPs and pro-inflammatory cytokines and promoting excessive angiogenesis [25].

C-X-C motif chemokine ligand (CXCL) 4, which is a platelet-derived chemokine, and CCL5 (RANTES) are both monocyte-attracting chemokines [55]. They can form a C-type CXCL4/CCL5 heterodimer that enhances CCL5-induced monocyte arrest, adhesion, and migration [56]. MKEY is a peptide inhibitor of CXCL4-CCL5 heterodimer formation that attenuates aortic diameter enlargement by inhibiting mural macrophage infiltration and angiogenesis [53]. Therefore, inhibiting macrophage functions and aggregation may mitigate AA/AD progression by improving angiogenesis.

Mast cells possess multiple biological functions, including innate immunity, participation in host defense mechanisms against parasitic infections, regulation of the immune system, tissue repair, and angiogenesis [57]. In human AAA samples, the number of infiltrated mast cells increased in the adventitia and outer media [34]; moreover, a study found that T cell activation, elastin levels, and angiogenesis were inhibited in mast cell-deficient mutant white spotting/white spotting (Ws/Ws) rats modeled by periaortic application of CaCl${}_2$ treatment [34]. Inhibition of mast cell degranulation plays a similar protective role against AAA [34]. This study suggests that mast cells and their granzymes are important inducers of angiogenesis and AAA. Furthermore, mouse mast cell protease-4 (mMCP-4) is a key trigger of angiogenesis and vascular cell apoptosis in AAA [58]. Mechanistically, mMCP-4 secreted by mast cells promotes aortic ring microvessel outgrowth via VEGF synthesis by ECs in a mouse aortic ring assay [58]. Therefore, the study emphasizes the critical role of mast cell chymase in AAA. Moreover, Zhang et al. [59] revealed that chemokine (C-C motif) receptor 2 (CCR2) is the key chemokine receptor for mast cell recruitment in Ang II-induced AAA lesions. Similarly, CCR2 knockout in mast cells protected from AAA by decreasing angiogenesis, macrophage and T cell infiltrations, and medial smooth muscle cell loss [59].

Eosinophils are innate immune cells that are rich in inflammatory cytokines, chemokines, and growth factors [60]. A clinical study suggested that eosinophil count is an independent risk factor for AAA incidence [61]. However, eosinophil gene knockout exacerbated AAA growth with increased inflammatory infiltration and angiogenesis in Ang II-induced Apoe${}^{-/-}$ mice [61]. Mechanistically, eosinophil-derived mouse eosinophil-associated-ribonuclease-1 and interleukin (IL)-4 trigger the polarization of macrophages from M1 to M2, resulting in ECM remodeling and wall weakening [61].

Type I interferons (IFNs) are cytokines commonly produced by immune cells following exposure to antigenic stimuli, including bacteria, viruses, autoantigens, and tumors [62]. IFN signaling through IFN receptors (IFNRs) initiates the immune-inflammatory reactions [62]. Compared with wild-type mice, IFNAR1 knockout mice showed mitigated neoangiogenesis, leukocyte accumulation, and time-dependent infrarenal aortic enlargement [63]. Therefore, IFNs are key cytokines in immune inflammation that are also associated with angiogenesis in AA/AD.

Kallistatin is a member of the serine proteinase inhibitor (SERPIN) family, which is associated with anti-inflammation, anti-oxidative stress, and anti-angiogenesis [64]. Treatment with recombinant human kallistatin or transgenic overexpression of the human kallistatin gene limited AAA progression in Ang II- and calcium phosphate-induced mouse models [65]. Although this study does not directly show that kallistatin can inhibit angiogenesis, the gene expression of VEGF in transgenic mice overexpressing the human kallistatin gene was lower than that in wild-type mice as well as in cultured VSMCs. Therefore, kallistatin might protect against AA/AD through anti-angiogenesis; however, this should be validated using an in vitro angiogenesis assay.

Similar to MMPs, cysteine cathepsins are commonly found in lysosomes, where they are involved in intra- and extracellular protein degradation [66]. Qin et al. [32] found that elastolytic cathepsin S gene knockout significantly reduced lesion adventitia microvessel content, inflammatory cell infiltration, and AAA formation in an Ang II infusion-induced mouse model. These results suggest that the degradation of ECM by proteases is closely related to angiogenesis.

HIF-1 consists of an oxygen-regulated $\alpha$ subunit and a constitutively expressed $\beta$ subunit, which regulate cell adaptation to hypoxia, such as migration, proliferation, survival, and angiogenesis [35]. Intervention with HIF-1$\alpha$ inhibitors limited angiogenesis, leukocyte infiltration, and aneurysm progression in an elastase-induced AAA mouse model. Similarly, another study showed that silencing of the HIF-1$\alpha$ gene alleviated aneurysm enlargement, angiogenesis, and expression of pro-angiogenic and pro-inflammatory factors [67], such as VEGF, Flt-1, MMP-2, and MMP-9, in an Ang II-infused AAA model. In addition, deferoxamine, which is a prolyl hydroxylase inhibitor, stabilizes HIF-1$\alpha$, augments MMP activities, and exacerbates the severity of Ang II-induced AAA [68].

Moreover, macrophage HIF-1$\alpha$ activation triggers vascular inflammation and AD progression by targeting metallopeptidase domain 17 (ADAM17) [36]. Besides macrophages, HIF-1 signaling in VSMCs also plays an essential role in angiogenesis [69]. Wang et al. [69] reported that cyclooxygenase-2 (COX-2) upregulated HIF-1$\alpha$/VEGF signaling, leading to angiogenesis and AAA formation in a CaCl${}_2$-induced mouse model; however, this biological process could be inhibited by quercetin, a flavonoid extracted naturally and has been validated to inhibit AAA progression by limiting oxidative stress and inflammatory response. Furthermore, a study included gene sequencing using microarrays for the emergency repair of ruptured AAA and open elective repair of AAA [70]. The upregulated genes, such as ANGPTL4, HILPDA, LOX, and SRPX2, involved in the processes of canonical HIF-1$\alpha$ signaling pathway network-related angiogenesis, are highly expressed in fibroblasts rather than in macrophages and VSMCs [70]. Previous studies have focused on the important roles of inflammatory cells and VSMCs in AA occurrence and development. Fibroblasts, which are the main cell component of the adventitia, are important in maintaining the stability of the arterial structure and function [71]. However, the pathological mechanisms of fibroblasts in AA/AD have rarely been reported. Therefore, angiogenesis may be a critical mechanism for exploring the role of fibroblasts in AA/AD. Taken together, HIF-1 is a potential target for hypoxia signaling pathway-related angiogenesis in AA/AD (Fig. 3).

The risk factors for AA/AD are similar to those for cardiovascular diseases; however, diabetes is an exception. Several studies have indicated that AA/AD risk is lower in patients with type II (insulin-resistant) diabetes than in healthy controls [72, 73, 74]. Therefore, researchers have focused on how diabetes inhibits AA/AD progression. Guo et al. [75] found an explanation that the pharmacological inhibition of prolyl hydroxylase reversed the impairment of HIF-1 expression and activity in diabetes and obviously counteracted the suppression of AAA enlargement by diabetes, with increased angiogenesis, leukocyte infiltration, and medial elastin and VSMCs destruction. Therefore, patients with diabetes have a lower risk, and the severity of AA/AD may result, at least partly, from dysregulated HIF-1-associated angiogenesis.

Cigarette smoking is the most dangerous environmental risk factor for AA/AD incidence and progression [76], and smoking individuals have a 2.5-fold greater risk for AAA than for atherosclerosis [77]. In AAA (n = 75) and control (n = 11) samples, all tissues exhibited increased angiogenesis-related gene expression and signs of oxidative stress during active smoking [78]. Several studies have shown that cigarette smoke or its extract inhibits prolyl hydroxylase, resulting in HIF-1 activation [79, 80], which may be a potential mechanism of angiogenesis induced by smoking. Moreover, cigarette smoke induces oxidative stress and reactive oxygen species, which in turn induces angiogenesis through HIF-1 [81]. Therefore, smoking leads to AA/AD involving angiogenesis through the hypoxia signaling pathway.

Chronic anemia and hypoxia are the principal inducers of production of erythropoietin (EPO), which is a critical cytokine regulating erythropoiesis and is synthesized in the kidneys [82]. Treatment with EPO monoclonal antibodies and EPO receptor (EPOR) gene knockdown (Epor${}^{+/-}$Apoe${}^{-/-}$) significantly reduced the incidence of AAA in an Ang II-induced mouse model [83]. Mechanistically, EPO induced endothelial migration, proliferation, and tube formation through the JAK2/STAT5 signaling pathway in vitro and ex vivo experiments [83]. Therefore, it is suggested that the hypoxia signaling pathway induces angiogenesis and may participate in the progression of AA/AD development.

Phosphatidylinositol-3-kinase (PI3K) signaling has multiple biological functions, such as cell differentiation, motility, survival, proliferation, and growth [84]. Previous studies have suggested that pan-PI3K inhibition leads to decreased levels of HIF-1$\alpha$, macrophage infiltration, and aneurysm dilatation in the aortas of porcine pancreatic elastase-infused rats [85]. However, systemic inhibition of pan-PI3K is associated with severe side effects, such as hepatotoxicity, stomatitis, pneumonitis, bone marrow suppression, hyperlipidemia, and hyperglycemia [86]. Furthermore, a recent study reported that treatment with IPI-549, which is a specific PI3K inhibitor, significantly inhibited angiogenesis and immune cell infiltration and prevented AAA formation in elastase-infused mice [85]. Mechanistically, IPI-549 treatment decreased AKT phosphorylation and HIF-1$\alpha$ levels; therefore, the PI3K/pAKT/HIF-1$\alpha$ signaling pathway is considered to play an essential role in AAA [85].

The VEGF family consists of five homologous genes, including VEGF-A, VEGF-B, VEGF-V, VEGF-D, and PGF [87], all of which are associated with angiogenesis and lymphangiogenesis. VEGF-A is an EC growth factor with a highly conserved cystine domain, heparin-binding site, and secreted signal peptide, which specifically binds to VEGFRs to play a biological role. The angiogenic effect of VEGF-A is mediated by VEGFR2 (Flt-1) and upregulated by inflammation, hypoxia, oxidative stress, wound healing, and other factors through transcriptional regulation mediated by various transcription factors, including HIF-1 (Fig. 3) [88, 89]. VEGF-A is one of the most potent angiogenic and vascular permeability factors that are essential in angiogenesis throughout life and are required for embryonic development [90, 91].

Kaneko H et al. [33] demonstrated that VEGF-A/Flt-1 signaling is important in CaCl${}_2$-induced AAA development by affecting both neovascularization and chronic inflammation. Injection with soluble Flt-1 (competitive inhibition of Flt-1) inhibited the infiltration of inflammatory cells, MMP activity, ECM degradation, and angiogenesis and finally alleviated AAA expansion [33]. Currently, the anti-VEGF-A monoclonal antibody, bevacizumab, is approved as an effective adjunctive therapy for solid tumors [92]. However, severe hypertension is a common adverse effect of bevacizumab [93]. Regardless of whether Flt-1 or bevacizumab is used, local rather than systemic medical treatment may be more suitable for future clinical trials. In addition to the biosynthetic drugs, curcumin, purified from the roots of Curcuma longa, was shown to inhibit VEGF expression and angiogenesis in the CaCl${}_2$-induced TAA model [23]. Therefore, curcumin may be a potential intervention in angiogenesis during AA/AD progression.

Notch activity is important for cell differentiation and involves angiogenesis by controlling the conversion of tip/stalk ECs [9]. The Notch pathway inhibits VEGFR2, VEGFR3, and NRP1 expression and enhances VEGFR1 expression [94]. The main function of VEGFR1 is to competitively bind to VEGF and inhibit VEGFR2 to regulate VEGF signaling in ECs [95]. The Notch intracellular domain (NICD) receptors depend on proteolytic cleavage by $\gamma$-secretase [96]. In AAA, dibenzazepine, which is a $\gamma$-secretase inhibitor, prevents Ang II-induced angiogenesis by inhibiting VEGF/VEGFR and HIF-1$\alpha$ expression [97]. Therefore, intervention in the Notch pathway appears to involve multiple mechanisms of vascular protection, including inflammation and angiogenesis [96].

The ANGPT system and its Tie2 receptor are related to the integrity and stability of the blood vessels [98]. ANGPT2 inhibits ANGPT1 by competitively binding to Tie2; therefore, ANGPT2 acts as an antagonist of ANGPT1 for Tie2 interaction. According to Yu’s report, recombinant ANGPT2 administration significantly inhibited angiogenesis, monocyte/macrophage infiltration, aortic dilatation, and rupture in an Ang II-induced ApoE${}^{-/-}$ mouse AA model [99]. Similarly, Chen et al. [100] analyzed the DNA methylation patterns of type A-AD and controls to explore epigenetic changes during AD progression. They found that DNA methylation of the ANGPT2 gene was lower in the AD testing and verification samples [100]. AD has a higher transcriptional activity of ANGPT2 because the hypermethylation of DNA leads to gene silencing. Finally, gene ontology (GO) analysis showed that angiogenesis was the most significant biological process [100]. Therefore, these results suggest that DNA methylation of ANGPT2 leads to angiogenesis and AD formation.

However, it has been suggested in atherosclerosis that ANGPT1/Tie2 play anti-angiogenic, anti-inflammatory, and anti-atherogenic roles [101, 102]. Several studies have revealed that the functions of ANGPT1 and ANGPT2 in atherosclerosis are complex and paradoxical [103, 104, 105, 106]. Therefore, the roles of these two molecules might involve functions other than antagonism.

Prostaglandin (PG) E2 is the most abundantly detected PG in various tissues biosynthesized by cyclooxygenase-1 (COX-1) or COX-2 and has four receptor subtypes (EP1-4). PGE2 is widely accepted to induce angiogenesis and inflammation in cancer and vascular diseases [107, 108]. COX-2 and the microsomal isoform of PGE synthase (mPGES-1) are involved in PGE2 synthesis, which is associated with vascular lesions in AAA [109]. Furthermore, a study demonstrated that PGE2 directly induces angiogenesis through EP4 in an in vitro angiogenesis assay [109]. Therefore, the COX-2/mPGES-1/PGE2/EP4 axis may be a potential intervention target for AAA-associated hypervascularization.

CXCL8, known as IL-8, is considered a pro-angiogenic factor that promotes chemotaxis and proliferation of ECs [110]; however, it has strong chemotactic effects on immune cells, particularly neutrophils. Therefore, CXCL8 can indirectly induce angiogenesis through chronic inflammation [111]. Blocking CXCL8 signaling by CXCR1/CXCR2 inhibitors (DF2156A) preserves the integrity of the vessel wall and inhibits leukocyte infiltration through the vasa vasorum [49].

MMPs belong to a family of proteolytic enzymes that degrade several components of the ECM. The pathological role of the MMP family in AA/AD, including MMP-1, -2, -3, -9, -12, -13, and -14, has been widely accepted [112, 113]. Of these MMPs, MMP-9 has been validated as a pro-angiogenic factor in AAA. However, lentiviral-mediated silencing of MMP-9 through RNA interference in human ECs failed to induce migration, proliferation, and tube formation in Matrigel matrix [114]. Therefore, MMP-9 regulates vascular remodeling by degrading ECM and promoting angiogenesis in AA/AD.

A previous study showed that aortic inducible nitric oxide synthase (iNOS) promotes NO expression, which plays a critical role in Ang II-induced AA and Marfan syndrome models [115]. A recent study showed that endothelial S-nitrosylation (SNO) modification promotes the development of thoracic aortic dissection (TAD) through plastin-3 (PLS3) SNO modification [116]. PLS3 SNO increased the production of the PLS3/plectin/cofilin complex, which enhanced cell migration and tube formation in an Ang II-treated EC angiogenesis assay [116]. Therefore, these results suggest that iNOS-generated NO promotes pathological angiogenesis and TAD formation by modifying endothelial PLS3 through SNO.