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Abdominal aortic aneurysm is a systemic and generalized arteriomegaly in mice and humans

Abstract

Although the pathogenesis of abdominal aortic aneurysm (AAA) remains largely unclear, evidence is accumulating to suggest the systemic nature of this disease. Here, we comprehensively assessed the whole aortic tree with its major branches based on computed tomography angiography (CTA) in AAA patients compared to ascending thoracic aortic aneurysm (ATAA) patients and nonaneurysmal controls, as well as in an original mouse model of AAA in Lkb1flox/flox;Myh11-Cre/ERT2 mice. The morphology and dimensions of the whole aorta (at different levels) and its major branches were compared among 47 AAA patients, 47 ATAA patients, and 46 nonaneurysmal controls based on CTA images. To further characterize AAA growth, tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice were generated. CTA, magnetic resonance imaging (MRI), and histopathological examination were performed to evaluate the morphology and dimensions of the whole aortic tree in Lkb1flox/flox;Myh11-Cre/ERT2 mice. The whole aorta extending from the sinotubular junction of the aortic root to the terminal aortic bifurcation, along with its major branches, was diffusely enlarged in AAA patients, whereas the dilatation was localized and restricted to the ascending aorta in ATAA patients. Lkb1flox/flox;Myh11-Cre/ERT2 mice spontaneously and progressively developed AAA, accompanied by aneurysms in renal artery, iliac artery, caudal artery, or femoral artery. Moreover, the mean cross-sectional diameters of the whole aortic tree with its major branches were diffusely larger in Lkb1flox/flox;Myh11-Cre/ERT2 mice compared with wild-type mice. This original morphologic study demonstrated that abdominal but not thoracic aortic aneurysm is a systemic and generalized arteriomegaly both in mice and humans.

Introduction

Aortic aneurysm is a permanent and localized pathological dilation of the aorta, exceeding the normal diameter by 50%1. There is epidemiologic and histologic evidence showing significant differences between abdominal aortic aneurysm (AAA) and thoracic aortic aneurysm (TAA)2. Although aortic aneurysm formation appears to be a focal event, patients with AAA often exhibit other aneurysms at sites remote from the abdominal aorta. Emerging studies have raised the suspicion that AAA is a systemic disease of the vasculature. However, whether only AAA (but not TAA) has this systemic tendency is unknown.

Arteriomegaly is defined as the diffuse ectasia of arteries with or without aneurysmal disease. It is characterized by significant dilation, tortuosity, elongation, and luminal irregularities with prolonged blood flow. The condition was first described by Leriche as “dolicho et mega artere” (elongated and enlarged arteries) in 19423, but it has received little attention until Thomas described the detailed angiographic findings and coiled the word arteriomegaly in 19714. Accumulating evidence has suggested that there exists generalized arteriomegaly in patients developing AAA5,6,7,8,9. Tilson et al. reported dilatation of the suprarenal abdominal aortas and iliac arteries in a series of patients with AAA5. With the use of ultrasonography in patients with and without AAA, Ward et al. found that the carotid, brachial, femoral, and popliteal arteries were all significantly enlarged in patients with AAA7. Moreover, several studies have reported statistically significant common carotid enlargement in patients with AAA8,9,10,11. However, all these observational studies have either a small number of cases or incomplete indicators to identify and characterize generalized arteriomegaly in AAA patients.

Moreover, the pathogenesis of AAA and generalized arteriomegaly is still poorly understood, because there is no reliable animal model of spontaneous AAA formation, and human studies rely on the use of established aneurysmal tissue which represents the end stage of a complex pathological process. Therefore, developing an ideal animal model for AAA and generalized arteriomegaly for translational use is of great importance.

In this present study, we comprehensively compared the mean cross-sectional diameter of the whole aortic tree with its major branches based on computed tomography angiography (CTA) images in patients with AAA and ascending thoracic aortic aneurysm (ATAA). We got convincing conclusion that AAA patients exhibit enlarged aorta and branch vessels throughout the whole arterial tree, whereas ATAA patients show localized aortic dilation which is restricted to the ascending aorta. In our previous study, we found that tamoxifen-inducible smooth muscle cell (SMC)-specific Lkb1 knockout mice (Lkb1flox/flox;Myh11-Cre/ERT2 mice) spontaneously developed AAA12. In order to further characterize generalized arteriomegaly and AAA formation, we utilized this ideal mouse model of AAA and combined CTA and magnetic resonance imaging (MRI) techniques. We found similar results to those from clinical patients that tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice that developed AAA exhibited generalized arteriomegaly and multiple aneurysms. Therefore, this present study provides extensive evidence from mice and humans that AAA (but not TAA) represents a localized manifestation of the systemic and generalized arteriomegaly.

Materials and methods

Ethics statement

This study was performed in accordance with relevant guidelines and regulations in Shanghai Chest Hospital affiliated to Shanghai Jiao Tong University School of Medicine. All methods were reported in accordance with ARRIVE guidelines.

Patients

The study included 140 consecutive patients undergoing computed tomography (CT) imaging. This cohort was generated from the most recent patients diagnosed of abdominal aortic aneurysm (AAA), patients diagnosed of ascending thoracic aortic aneurysm (ATAA), and a group of control patients. Aortic aneurysms are defined as focal dilatations of the aorta that are 50% greater than the proximal normal segment. Patients in the aneurysm groups were excluded if they had a known congenital connective tissue disorder, or if their aneurysm was as consequence of aortic dissection. The control group was identified from the most recent consecutive individuals who had undergone CT imaging of the entire aorta during routine medical checkups. The exclusion criteria for controls included confirmed aneurysms, age < 50 years, or low image quality cases. All patients’ risk factors were identified by examination of their computer-based medical record. Human research was performed in line with the principles of the Declaration of Helsinki. Research protocols were approved by the Medical Ethics Committee of the Shanghai Jiao Tong University School of Medicine, and all subjects gave written informed consent.

Patient vessel measurements

A retrospective analysis of CT angiograms was conducted within a timeframe from September, 2015 to April, 2021. Images were reviewed using a CVI42 software (Release 5.13 version, Circle Cardiovascular Imaging Inc., Calgary, Alberta, Canada). The inclusion criteria for CTA imaging of the entire aorta are clear imaging, while the exclusion criteria are severe imaging artifacts that cannot be effectively measured. The entire aorta was studied, extending to include the aortic arch trifurcation and common iliac arteries. For each imaging plane, aortic diameters were measured at eight levels: (1) 1 cm distal to the sinotubular junction (STJ); (2) in the origin site of innominate artery; (3) in the origin site of left common carotid artery; (4) 1 cm distal to the origin site of left subclavian artery; (5) descending aorta (at the T4 level); (6) abdominal aorta (in the origin site of celiac trunk); (7) abdominal aorta (1 cm distal to the origin site of right renal artery in human); and (8) abdominal aorta (1 cm proximal to the aortic bifurcation).

Measurement of the left common carotid artery (LCCA), celiac trunk, left renal artery (LRA), left and right common iliac artery (LCIA and RCIA), and aorta at consistent anatomic landmarks and orientations was performed on the CVI42 software (vascular module). The aortic/arterial diameters were manually measured by two independent investigators who are not aware of the purpose of the experiments and have over 5 years of experience in cardiovascular imaging. The measurement method involves manually selecting the center points of multiple planes, and the software automatically generates an axis. The plane perpendicular to this axis is used to measure the cross-section of the aorta. After manually selecting the measurement plane, the software automatically generates the area, perimeter, maximum diameter, and minimum diameter of the plane. Each vessel diameter was measured from the outside wall to the outside wall. All measurements were taken from pretreatment scans when the aortic aneurysm size warranted treatment.

Animals

Myh11-Cre/ERT2 transgenic mice (Stock No. 019079) and Lkb1-floxed (Lkb1flox/flox) mice (Stock No. 014143) were both on the background of C57BL/6J background and purchased from The Jackson Laboratory. Myh11-Cre/ERT2 mice were intercrossed with Lkb1flox/flox mice to generate Lkb1flox/flox;Myh11-Cre/ERT2 mice. Lkb1flox/flox;Myh11-Cre/ERT2 aged 5–6 weeks were intraperitoneally injected with 100 µl tamoxifen solution (1 mg in 100 µL sunflower oil per mouse) for 5 consecutive days to specifically activate Cre recombinase in mature VSMCs. Mice were housed in a controlled environment (22 °C, 12-h/12-h light/dark cycle) with free access to food and water.

Tissue collection and processing

Mice were euthanized by inhalation of 5% isoflurane and cervical dislocation where appropriate. Tissue sections for pathological diagnosis were fixed in 10% neutral buffered formalin and embedded in paraffin. Paraffin-embedded sections were cut at 5 μm thickness and stained with hematoxylin and eosin (H & E) according to standard protocols13,14.

Contrast-enhanced micro-CT scanning imaging

Prior to any micro-CT examinations, mice were placed in an acrylic glass box and anesthesia was delivered via inhalation of 2% isoflurane. As soon as the desired depth of anesthesia was reached, verified by an absence of the paw and corneal reflex, a catheter was inserted into the lateral tail vein. This catheter was used to deliver 100–150 µL of a blood pool contrast agent (ExiTron nano 12000, nanoPET Pharma GmbH, Berlin, Germany). The animals were transferred to the mouse bed in the system while anesthesia was ensured by a constant flow of 2% isoflurane.

Every mouse began imaging immediately after injection of the contrast agent, and was analyzed by SkyScan 1176 (Bruker MicroCT, Kontich, Belgium). The 1.7.1.0 version of NR econ software was used for three-dimensional (3D) reconstruction and viewing of images. After 3D reconstruction, the segmentation was divided into three parts by means of DataViewer64 software (Bruker):1) thoracic part which is from top image to the level of diaphragm; 2) abdominal part which is from the level of diaphragm to the aortic bifurcation; 3) pelvic part which is from the aortic bifurcation to the bottom image. After segmentation, the divided image data are converted to a DICOM format using the DicomCT software and analyzed by the CVI42 software (vascular module).

Aortic diameters were measured at six levels: (1) 1 cm distal to the sinotubular junction (STJ); (2) in the origin site of left common carotid artery; (3) descending aorta (at the apex of mice heart level); (4) abdominal aorta (in the origin site of celiac trunk); (5) abdominal aorta (1 cm distal to the origin site of left renal artery in mice); and (6) abdominal aorta (1 cm proximal to the aortic bifurcation). The medium arteries measurement included LCCA, celiac trunk, LRA, right renal artery (RRA), LCIA, RCIA, left femoral artery (LFA) and right femoral artery (RFA).

In vivo magnetic resonance imaging (MRI) studies

All MRI scans were performed on a BioSpec 70/20 USR MRI scanner (Bruker BioSpec 70/20, USR, Bruker Biospin, Ettlingen, Germany). Each mouse was induced and maintained under isoflurane anesthesia (2%) in medical-grade air and monitored using the small animal instrument monitoring and gating system for respiration rate (reduced respiratory rate to 40 breath/min). All animals were placed in the supine position.

For MRI angiography, the abdominal aortic trees were imaged using a three-dimensional fast low-angle shot (3D-FLASH) sequence. Images were analyzed using the ParaVision Acquisition software (PV6.0.1, Bruker, Germany) and CVI42 software (vascular module). Aortic diameters were measured at five levels: (1) 1 cm distal to the origin site of left subclavian artery; (2) descending aorta (at the apex of mice heart level); (3) abdominal aorta (in the origin site of celiac trunk); (4) abdominal aorta (1 cm distal to the origin site of left renal artery in mice); and (5) abdominal aorta (1 cm proximal to the aortic bifurcation). The medium arteries measurement included celiac trunk, LRA, RRA, LCIA, RCIA, LFA, RFA and tail artery (TA).

Statistical analysis

Unpaired two-tailed Student’s t-tests were used to calculate significant differences between two groups. Multiple comparison correction analysis was performed using one-way ANOVA with Tukey’s post hoc HSD test. The incidence of risk factors between groups was compared using two by three contingency tables applying χ2 analysis. P < 0.05 was considered statistically significant. All values are expressed as mean ± SD.

Results

Patient characteristics

The study group consisted of 47 AAA patients, 47 ATAA patients, and 46 nonaneurysmal controls. Patient characteristics of each group are listed in Table S1. The patients with AAA were significantly older than ATAA patients and controls. The patients with AAA or ATAA appeared well matched with the control group for gender. A higher incidence of cigarette smoking, hypertension, and hyperlipidemia were seen in AAA group compared with control group.

Diffuse aortic dilatation in AAA patients, but not ATAA patients

The mean aortic diameters measured by helical CT at multiple fixed levels, extending from the sinotubular junction (STJ), aortic arch, descending aorta, abdominal aorta, to the terminal aortic bifurcation, were compared among AAA patients, ATAA patients, and nonaneurysmal controls (Fig. 1B and Table S2). Among these three groups, the mean aortic diameters were largest at the levels of STJ and in the origin sites of brachiocephalic trunk and left common carotid artery (LCCA) in ATAA group (Fig. 1A,C, and Figure S1). However, no significant difference in the mean aortic diameters at other measurement sites was seen between ATAA and control groups (Fig. 1A,C, and Figure S1). Notably, the mean cross-sectional aortic diameters of the whole aorta (at all 8 measurement sites) in patients with AAA were significantly and diffusely larger than control group (Fig. 1A,C, and Figure S1). Taken together, these data suggest that the whole aorta exhibited diffuse arteriomegaly in patients with AAA, whereas aortic dilatation was localized and restricted to ascending thoracic aorta in ATAA patients.

Fig. 1

figure 1

Diffuse aortic dilatation in AAA patients, but not ATAA patients. (A) Representative three-dimensional (3D) reconstruction and conventional CTA images of the whole aorta and cross-sections of different aortic levels in AAA patients, ATAA patients and nonaneurysmal controls. Scale bars: 25 mm for whole aorta; 10 mm for L1-L8 sections. (B) Diagram showing sites of aorta measurement. (C) Analysis of mean aortic diameter in different aortic levels of AAA patients, ATAA patients and nonaneurysmal controls using CTA (nControl = 46, nAAA = 47, nATAA = 47). *P < 0.05 vs. control group, #P < 0.05 vs. control group. P values were determined using one-way ANOVA with Tukey’s post hoc HSD test (C). AAA abdominal aortic aneurysm, ATAA ascending thoracic aortic aneurysm, CTA computed tomography angiography.

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Diffuse dilatation of medium arteries in patients with AAA

To further investigate the medium arteries remote from the aneurysms, the mean arterial diameters of the major aortic branches, including LCCA, celiac trunk, renal artery, common iliac artery, and common femoral artery, were compared in different groups of patients based on CTA images. The mean arterial diameters of all measured branch vessels in patients with AAA were significantly larger than nonaneurysmal controls (Fig. 2). However, the ATAA group did not demonstrate any significant diameter changes in branch vessels relative to controls, except that there was significantly enlarged LCCA which is closest to the ascending thoracic aorta where aneurysms formed (Fig. 2). The results presented here further delineate a systemic dilatation of the vasculature in AAA patients, but a relatively localized dilatation of the vasculature in ATAA patients.

Fig. 2

figure 2

Diffuse dilatation of medium arteries in patients with AAA. Analysis of mean arterial diameter in left common carotid artery (LCCA), celiac trunk, left renal artery (LRA), left and right common iliac arteries (LCIA and RCIA) of AAA patients, ATAA patients and nonaneurysmal controls (nControl = 46, nAAA = 38–47, nATAA = 31–47). *P < 0.05 vs. control group; #P < 0.05 vs. control group; *NS* not significant (*P* > 0.05 vs. control group). P values were determined using one-way ANOVA with Tukey’s post hoc HSD test.

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Generalized arteriomegaly and multiple aneurysms in tamoxifen-inducible Lkb1 flox/flox;Myh11-Cre/ERT2 mice which developed AAA

We previously generated mice with tamoxifen-inducible SMC-specific Lkb1 deletion (Lkb1SMiKO) by intercrossing Lkb1flox/flox mice with Myh11-Cre/ERT2 mice (Fig. 3A)12. We found that Lkb1SMiKO mice spontaneously and progressively developed AAA, accompanied by aneurysms in iliac artery, femoral artery, and popliteal artery12, which is highly reminiscent of human aneurysm of the aorta-iliac-femoral2. We believed that this is an ideal and clinically significant animal model to capture the trajectory of arterial aneurysm formation that resembles human anatomy and pathophysiology. Therefore, we utilized CTA and MRI techniques to investigate the pathogenesis of AAA in this animal model.

Fig. 3

figure 3

Diffuse dilatation of the whole aorta in tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice which spontaneously developed AAA. (A) Schematic diagram of the generation of Lkb1flox/flox;Myh11-Cre/ERT2 mice (Lkb1SMiKO mice). (B) Representative images of aneurysms in abdominal aorta, iliac arteries, and femoral arteries in Lkb1SMiKO mice. Black circles denote the femoral arterial aneurysms. (C) Representative CTA images with three-dimensional (3D) reconstruction of the whole aorta and cross-sections of different aortic levels in wild-type (WT) and Lkb1SMiKO mice. Scale bars: 5.0 mm for whole aorta; 1.0 mm for L1-L6 sections. (D) Diagram showing sites of aorta measurement. (E) Analysis of mean aortic diameter in different aortic levels of WT and Lkb1SMiKO mice. N = 5–7 for each group. *p < 0.05. P values were determined using student’s t-test (E).

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Consistent to our previous results, we found that almost all Lkb1SMiKO mice developed multiple aneurysms in abdominal aorta, iliac artery, and/or femoral artery (Fig. 3B). Using CTA with three-dimensional (3D) reconstruction, we found that Lkb1SMiKO mice that developed AAAs exhibited generalized arteriomegaly and multiple aneurysms (Fig. 3C). The mean aortic diameters at multiple levels, extending from the ascending thoracic aorta, aortic arch, descending aorta, abdominal aorta (in the origin sites of celiac trunk and renal artery), to the terminal aortic bifurcation (Fig. 3D), were significantly and diffusely larger in Lkb1SMiKO mice compared with wild-type (WT) mice (Fig. 3C,E).

To further investigate the medium arteries, the mean arterial diameters of the major aortic branches were compared between WT and Lkb1SMiKO mice, including LCCA, celiac trunk, left and right renal artery (LRA and RRA), left and right common iliac arteries (LCIA and RCIA), and left and right femoral arteries (LFA and RFA). The mean arterial diameters of all measured branch vessels in Lkb1SMiKO mice were significantly larger than WT control mice (Fig. 4A,B). Aneurysm ruptures in iliac artery (Figure S2A), renal artery (Figure S2B), and femoral artery (data not shown) occurred frequently in Lkb1SMiKO mice. These data demonstrate that deletion of Lkb1 specifically in mature VSMCs gradually caused generalized arteriomegaly and multiple aneurysms.

Fig. 4

figure 4

Diffuse dilatation of medium arteries in tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice. (A) Representative CTA images of celiac trunk, right renal artery (LRA), right common iliac arteries (RCIA), and right femoral arteries (RFA) in wild-type (WT) and Lkb1SMiKO mice. Scale bars: 1.0 mm. (B) Analysis of mean arterial diameter in left common carotid artery (LCCA), celiac trunk, left and right renal artery (LRA and RRA), left and right common iliac arteries (LCIA and RCIA), and left and right femoral arteries (LFA and RFA) in WT and Lkb1SMiKO mice. N = 5–7 for each group. *p < 0.05. P values were determined using student’s t-test (B).

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Progressive aortic or arterial dilatation in tamoxifen-inducible Lkb1 flox/flox;Myh11-Cre/ERT2 mice

To confirm those findings, we further checked the morphology of different segments of aorta and different medium arteries in Lkb1SMCiKO mice at different time points (1.5 and > 3.0 months) after tamoxifen induction. H & E staining analysis revealed the progressive dilation of the abdominal and ascending thoracic aortas (Fig. 5A). We also found significantly dilated carotid arteries and femoral arteries in Lkb1SMiKO mic (Fig. 5A,B), which was consistent with the CTA data. Moreover, Lkb1SMCiKO mice showed a significant increase in aorta length compared to WT control mice (Fig. 5C). These findings suggest that Lkb1SMCiKO mice developed generalized arteriomegaly characterized by diffuse dilation and significant elongation of the whole aortic tree.

Fig. 5

figure 5

Histopathological results indicate the progressive aortic or arterial dilatation in tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice. (A) H & E staining of thoracic aorta, abdominal aorta, and femoral artery in WT and Lkb1SMiKO mice at 1.5 and > 3.0 months (1.5 M and > 3.0 M, respectively) post-tamoxifen induction. Scale Bar: 200 μm for thoracic aorta and abdominal aorta; 100 μm for femoral artery. (B) Quantification of the external elastic laminae (EEL) perimeter of the thoracic aorta (TA), abdominal aorta (AA), carotid artery (CA), and femoral artery (FA) from WT and Lkb1SMiKO mice at 1.5 months post-TAM induction. N = 6 and n = 8 for WT and Lkb1SMiKO mice, respectively. (C) Quantification of the aortic length from WT and Lkb1SMiKO mice. N = 5 and n = 8 for WT and Lkb1SMiKO mice, respectively. P values were determined using student’s t-test (B and C). For all panels, *p < 0.05.

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We further used MRI to confirm the results we found. We found that even in Lkb1SMCiKO mice which haven’t developed aortic or arterial aneurysms yet, the mean aortic diameters at multiple levels were significantly enlarged compared with WT mice (Fig. 6A,B). Lkb1SMCiKO mice which developed AAA after tamoxifen induction were frequently accompanied by aneurysms in iliac artery, femoral artery, and even caudal artery (Fig. 6C,D). Notably, we found that the mean arterial diameter of caudal artery in Lkb1SMCiKO mice was dramatically larger than WT control mice (Fig. 6D). Altogether, these results from mice further confirm that AAA is a systemic dilatation of the whole vasculature.

Fig. 6

figure 6

Generalized arteriomegaly and multiple aneurysm formation in tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice. (A) Representative Magnetic Resonance Imaging (MRI) images of aortas in wild-type (WT) and Lkb1SMiKO mice. Scale bars: 1.0 mm. (B) Analysis of mean aortic diameter WT and Lkb1SMiKO mice. N = 6–7 for each group. (C) Representative MRI images showing aneurysms in iliac arteries Lkb1SMiKO mice. Scale bars: 5.0 mm. (D) Representative MRI images showing aneurysms in caudal artery in Lkb1SMiKO mice and analysis of mean arterial diameter of caudal arteries in WT and Lkb1SMiKO mice. Scale bars: 1.0 mm. N = 6 and n = 15 for WT and Lkb1SMiKO mice, respectively. P values were determined using student’s t-test (B and D). For all panels, *p < 0.05.

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Discussion

In this present study, we demonstrated that AAA is a systemic disease of the whole vasculature, whereas ATAA is a relatively localized aortic disease. We further introduced an ideal and clinically significant animal model of AAA which was originally developed by us12 and found similar results to those from clinical patients that AAA is associated with generalized arteriomegaly and multiple aneurysms. Generalized arteriomegaly with AAA formation is a progressive disease affecting the whole arterial tree.

To our knowledge, this is the first study to comprehensively investigate the whole aortic tree with its major branches in AAA and ATAA patients and mice. We comprehensively assessed the mean cross-sectional diameter of the whole aortic tree extending from the STJ of the aortic root to the terminal aortic bifurcation (totally 8 fixed levels) based on CTA images in AAA patients, ATAA patients, and nonaneurysmal controls. Notably, AAA patients exhibited diffuse enlargement of whole aortic tree in all 8 levels compared with nonaneurysmal controls, whereas ATAA patients showed aortic dilatation only limited to the ascending aorta. The medium arteries were consistently and diffusely enlarged in AAA patients, whereas no differences were found in ATAA patients compared with nonaneurysmal controls, except the LCCA. These data convincingly demonstrate the systemic nature of AAA, but localized nature of ATAA, suggesting the different pathogenesis between AAA and TAA.

We further utilized an original mouse model of AAA to capture the trajectory of AAA formation. We found that Lkb1SMiKO mice developed generalized and progressive arteriomegaly throughout the arterial tree, followed by aneurysmal formation within the abdominal aorta and in other arteries in the advanced stage. These findings suggest that generalized arteriomegaly and AAA formation are two distinct manifestations or two different stages of the same disorder affecting the structural integrity of all arteries. This is consistent with the fact from clinical patients that arteriomegaly begins at an earlier age than aneurysmal disease15. As observed by Barandiaran, the majority of arteriomegalic patients who had no aneurysmal disease at presentation developed multiple aneurysms at different levels of the aorta-iliac-femoral tree16. Therefore, AAA is a representative manifestation of a generalized systemic abnormality in the arterial wall.

Previous studies have demonstrated that TAAs and AAAs share some similar pathological phenotypes, but display some important differences in the pathogenesis of these two types of aneurysms17. The regional distribution of VSMCs of different embryonic origins is speculated to cause region-specific aortopathies. Therefore, we speculate that segment-specific distribution of heterogeneous VSMCs likely contributes to the different characteristics between ATAAs and AAAs. Our new animal model helps to understand the pathogenesis of generalized arteriomegaly with localized aneurysm formation. In our previous study12, we demonstrated that progressive VSMC transformation and subsequent extracellular remodeling are the driving force for aortic or arterial aneurysm formation. Further work is needed to fully understand the exact pathogenesis of generalized arteriomegaly and AAA formation. Although no distinct genetic components have been identified in clinical patients with AAA to date, reports have suggested a strong familial link with regard to arteriomegaly and aneurysm development18. Our previous and present findings together implicate genetic mutations or defects that cause loss of VSMC fate in the pathogenesis of generalized arteriomegaly and AAA formation.

Several study limitations should be considered. As the aortic diameter is strongly related to body size19, it is recommended that the aortic size should be standardized by body surface area. However, due to the retrospective nature of this study, the aortic size in patients was not standardized by body surface area. For the aortic size in mice, external elastic laminae (EEL) data can be inaccurate due to the angle at which the sections are cut or the shape of the lumen. Other limitations of this study include its retrospective design and small sample size. Future prospective multicenter studies with larger cohorts are recommended to further validate our findings.

Conclusion

In conclusion, the present study confirms the concept that AAA progression can be regarded as a localized manifestation of a generalized systemic abnormality in the vasculature which is characterized by generalized arteriomegaly and multiple aneurysms. Moreover, we further demonstrate that tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 mice can be used as an ideal and clinically significant animal model to investigate generalized arteriomagaly with localized AAA formation that resembles human anatomy and pathophysiology. We look forward to future translational work based on this original mouse model.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the National Natural Science Foundation of China (Grant Numbers: 82130012, 82300489, and 81830010), the Shanghai Pujiang Program (No. 23PJD084), the Nurture projects for basic research of Shanghai Chest Hospital (Grant Number: 2022YNJCQ03) and the Innovative Research Team of High-level Local Universities in Shanghai (Grand number: SHSMU-ZLCX20212302). The funders had no role in the study design, data collection, data analyses, interpretation, or writing of the manuscript.

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Author notes

Zhaohua Cai and Liang Fang contributed equally to this work.

Authors and Affiliations

Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

Zhaohua Cai, Liang Fang, Min Liang, Yangjing Jiang, Yijie Huang, Haiping Chen, Yunwen Hu, Danrui Xiao, Feng Liang, Huanhuan Huo & Ben He

Department of Osteoporosis and Bone Disease, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200033, China

Zhanying Wei

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Zhaohua Cai

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