Skip to main content
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes Care
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care in Diabetes
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • ADA Scientific Sessions Abstracts
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • ADA Scientific Sessions Abstracts
    • Diabetes COVID-19 Article Collection
    • Diabetes Symposium 2020
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Submit Cover Art
    • ADA Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Obesity Studies

Perivascular Adipose Tissue–Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity

  1. Ze-Bei Zhang,
  2. Cheng-Chao Ruan⇑,
  3. Jing-Rong Lin,
  4. Lian Xu,
  5. Xiao-Hui Chen,
  6. Ya-Nan Du,
  7. Meng-Xia Fu,
  8. Ling-Ran Kong,
  9. Ding-Liang Zhu and
  10. Ping-Jin Gao⇑
  1. The State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension, Ruijin Hospital and Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
  1. Corresponding author: Ping-Jin Gao, gaopingjin{at}sibs.ac.cn, and Cheng-Chao Ruan, ccruan{at}sibs.ac.cn.
  1. Z.-B.Z. and C.-C.R. contributed equally to this work.

Diabetes 2018 Aug; 67(8): 1549-1560. https://doi.org/10.2337/db18-0098
PreviousNext
  • Article
  • Figures & Tables
  • Suppl Material
  • Info & Metrics
  • PDF
Loading

Abstract

Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice (ob/ob) and high-fat diet–induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet-derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice. Therefore, we hypothesized that PDGF-D mediates adventitial inflammation, which provides a direct link between PVAT dysfunction and AA formation in AngII-infused obese mice. We found that PDGF-D promotes the proliferation, migration, and inflammatory factors expression in cultured adventitial fibroblasts. In addition, the inhibition of PDGF-D function significantly reduced the incidence of AA in AngII-infused obese mice. More importantly, adipocyte-specific PDGF-D transgenic mice are more susceptible to AA formation after AngII infusion accompanied by exaggerated adventitial inflammatory and fibrotic responses. Collectively, our findings reveal a notable role of PDGF-D in the AA formation during obesity, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

Introduction

A close relationship has been well established between obesity and vascular diseases, including hypertension, atherosclerosis, and aortic aneurysm (AA) (1–3). In addition to metabolic effects, adipose tissue–derived adipokines perform various important roles in the regulation of vascular disorders such as neointimal formation, angiogenesis, and vascular remodeling (4–6). Virtually all arteries are surrounded by amounts of perivascular adipose tissue (PVAT), which is juxtaposed to the vascular adventitia. Recently, it has become recognized that PVAT is abundantly expanded with an altered production of adipokines and chronic inflammatory response during obesity, which have important effects on vascular disease (7–9).

AA, characterized by chronic vascular inflammation and destructive connective tissue remodeling, tends to expand asymptomatically until a catastrophic event, such as aortic rupture or dissection, occurs (10,11). Multiple risk factors are associated with the incidence of AA, including advanced age, smoking, hyperlipidemia, and hypertension (12,13). Recently, obesity is reported to increase the risk of abdominal AA. A population study of >12,000 men confirmed that an index of obesity (waist circumference and waist-to-hip ratio) independently associates with abdominal AA formation (14). Another cohort study (15) suggested that the risk of abdominal AA increased by 15% per 5-cm increment of waist circumference up to 100 cm for men and 88 cm for women. A previous study (16) has pointed out increased AA formation in leptin-deficient obese mice (ob/ob) after angiotensin II (AngII) infusion. However, little is known about the detailed mechanism of AA formation during obesity.

Vascular inflammation is a crucial cause of AA, which is histologically characterized by medial degeneration and various degrees of adventitial immune cell recruitment (17). The infiltration of inflammatory cells, including macrophages, lymphocytes, and mast cells, is mainly observed in the tunica adventitia of human aneurismal tissues (18). Recent studies showed that adventitial fibroblast activation contributes to AA formation via accelerating immune cell–mediated vascular inflammation in mice (19,20). It is also well known that chronic low-grade inflammation within the adipose tissue is an important causal factor for obesity-related vascular disorders (21–23). Therefore, we hypothesized that PVAT-derived factor mediates adventitial inflammation and promotes AA formation in AngII-infused obese mice.

In the current study, by performing cDNA microarray analysis, we detected highly expressed platelet-derived growth factor-D (PDGF-D) in the PVAT of AngII-induced ob/ob mice. PDGF-D stimulated adventitial fibroblast migration and proliferation, as well as inflammatory factor expression. Blockade of PDGF-D function prevented AA formation in obese mice with AngII infusion. More importantly, we further demonstrated the pivotal role of PDGF-D in AA formation by using an adipocyte-specific PDGF-D transgenic mouse model.

Research Design and Methods

Animals and Animal Care

Male 8-week-old ob/ob mice and wild-type (WT) mice were purchased from Slac Laboratory Animal Co., LTD. High-fat diet (HFD)–induced obese mice were fed a diet containing 60% kcal from fat for 4 months before and during the infusion of AngII. Mice in the normal diet group (low-fat diet) were age matched to the HFD mice to control for effects of aging. Mice were infused with PBS or 1,000 ng/kg/min AngII using ALZET Mini-Pumps for 14 days. For in vivo PDGFR-D inhibition experiment, mice were treated via oral gavages (CP673451; 40 ng/kg/day) for 14 days during AngII infusion. Systolic blood pressure was measured by the tail-cuff method, and the average of three pressure readings was obtained. All animals had free access to water and a standard laboratory diet. All animal procedures were approved in accordance with the institutional guidelines established by the Committee of Ethics on Animal Experiments at the Chinese Academy of Sciences.

Gene Expression Microarrays

Whole-mouse genome microarray 4 × 44 K was purchased from Agilent. Data were scanned by an Agilent Microarray Scanner using the default settings and were analyzed by the Shanghai Biotechnology Corporation.

Ultrasound Examination

The aortic internal diameter of mice was assessed by a VisualSonics Vevo770 Ultrasound biomicroscope (VisualSonics Inc., Toronto, ON, Canada) with a 30-MHz linear array ultrasound transducer, and the inner lumen diameter at the maximal expanded portion of the aorta was quantified as the internal maximal diameter.

Generation of Adipocyte-Specific Transgenic Mice

A mouse pdgfd open reading frame was inserted into the PiggyBac transposon gene expression vector after the adipocyteprotein-2 promoter. Then, transgenic mice were generated by vector microinjection to the zygote. The pups were screened by PCR assay. Of 52 pups screened, 13 were identified positive (F0). F1 was generated by each F0 mating with WT mice with the same C57BL/6 background. F1 was identified by PCR and Western blot.

Histology and Immunostaining

Aortas fixed in formalin and embedded in paraffin were sectioned at 5 μm. Hematoxylin-eosin (H-E) or Masson’s trichrome staining was performed using standard procedures. Immunohistochemical staining of PDGF-D was performed using anti–PDGF-D antibody. Antigen retrieval was obtained by heating the tissue slides in 0.01 mol/L citrate buffer, pH 6.0, at 100°C for 5 min. Immunofluorescence staining of Ki67, CD68, α-smooth muscle actin (α-SMA), and fibroblast-specific protein 1 (FSP1) was performed using anti-Ki67 (ab15580; Abcam), anti-CD68 (MCA1957; Bio-Rad), anti–α-SMA (ab21027; Abcam), and anti-FSP1 (ab124805; Abcam) antibodies, and then fluorescence-conjugated secondary antibodies (Alexa Fluor 555, Alexa Fluor 488; Invitrogen). Sections were mounted in Fluorescence Mounting Medium (Dako). Images of H-E and immunohistochemical staining were obtained by Zeiss microscope. Immunofluorescence staining was examined by a laser-scanning confocal microscope (Zeiss). Images were analyzed with ImageJ and Image-Pro Plus software.

Cell Culture

For adipocyte culture, stromal vascular fraction cells in the subcutaneous adipose tissue were separated from adipocyte-specific PDGF-D transgenic (PA-Tg) mice and WT mice by a collagenase digestion method. Then stromal vascular fraction to adipocyte differentiation assay was performed by treatment with DMEM containing 10% FBS, 0.5 mmol/L isobutylmethylxanthine, 0.1 μmol/L dexamethasone, 1 μmol/L rosiglitazone, and 1 μg/mL insulin for 2 days, followed by treatment with 1 μg/mL insulin for 8 days. At day 10, PA-Tg–conditioned medium (PA-Tg-CM) and WT adipocyte–conditioned medium (WT-CM) were collected to culture adventitial fibroblasts. Rat adventitial fibroblasts were isolated from the aortas of Sprague-Dawley rats (weight 120–150 g) and cultured in conditioned medium at 37°C in a humidified atmosphere containing 5% CO2.

Quantitative Real-time PCR and Western Blot Analysis

Quantitative real-time PCR (QPCR) was performed using the SYBR Premix Ex Taq kits (TaKaRa) in an ABI PRISM 7900HT System (Applied Biosystems). Succinate dehydrogenase complex subunit A was used as a standard reference. Reactions were performed at 95°C for 30 s followed by 40 cycles at 95°C for 5 s, and at 60°C for 30 s. Mouse tissue or cell extracts containing equal amounts of total protein were resolved by SDS-PAGE followed by immunoblot with the immunoblotting antibodies (e.g., PDGF-D, transforming growth factor-β [TGF-β], SMAD2/3). The chemiluminescence was detected using an ECL detection system.

Adventitial Fibroblast Migration and Proliferation Assay

Migration assays were performed using 6.5-mm-diameter and 8.0-μm-pore size Transwells (Costar) coated with 0.5% gelatin. Adventitial fibroblasts were prepared in serum-free medium, and 4 × 104 cells were added to the upper chamber in migration buffer (DMEM containing 0.1% BSA). After 24 h of AngII or PDGF-D stimulation at 37°C, cells were removed from the upper surface of the membranes with a cotton swab, and cells that migrated to the lower surface were fixed with 4% paraformaldehyde for 30 min and then stained with 0.1% crystal violet (C6158; Sigma-Aldrich) for 10 min. Migrated cells were then counted under a microscope. Cell proliferation assays were performed using Cell-Light EdU Apollo594 In Vitro Imaging Kit (Ribobio Co., LTD.). Images were obtained by a laser-scanning confocal microscope (Zeiss).

ELISA

Adventitial fibroblasts were seeded into six-well plates and incubated in serum-free DMEM for 24 h. The cells were stimulated for indicated stimulations. Interleukin-6 (IL-6), MCP-1, and tumor necrosis factor-α in the supernate, and plasma was quantified using sandwich ELISA kits according to the protocol provided by the manufacturer (Abcam).

Statistics

Results were expressed as the mean ± SD. Comparisons of experimental groups were analyzed by Student t test (two groups) or one-way ANOVA followed by the post hoc Dunnett test for data with more than two groups (Levene tests for equal variance). The Dunnett T3 test was used as a post hoc test comparison for the analysis of unequal variances (Welch and Brown-Forsythe test). Probability values <0.05 were considered to be statistically significant.

Results

AngII Induces AA Formation and Adventitia Activation in Obese Mice

Initially, we found that ob/ob mice manifest a phenotype of AA when subjected to 2 weeks of infusion of AngII (Fig. 1A). The AA incidence in AngII-infused ob/ob mice was 65% (13 of 20) compared with 5% (1 of 20) in WT mice. Among the 13 occurrences of AA in ob/ob mice, 7 were abdominal AA, 5 were thoracoabdominal AA, and 1 was thoracic AA (Fig. 1B). Approximately 30% (6 of 20) of the ob/ob mice died because of aortic rupture, whereas none of the WT mice died (Fig. 1C). Ultrasound analysis showed aortic expansion in ob/ob mice compared with WT mice after AngII infusion (Fig. 1D). Furthermore, AngII infusion resulted in a comparative increase of media thickness in WT and ob/ob mice, whereas adventitia in ob/ob mice was remarkably thickened compared with WT mice after AngII infusion (Fig. 1E), which is accompanied with an increased macrophage infiltration (Fig. 1F). Next, we also demonstrated that AngII caused AA formation in HFD-induced obese mice, including abdominal AA, thoracoabdominal AA and thoracic AA (Supplementary Fig. 1A–C). Accordingly, AngII-infusion resulted in adventitial thickening and macrophage infiltration in HFD mice (Supplementary Fig. 1D and E). These indicate that adventitia activation may be involved in the AA formation during obesity.

Figure 1
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1

AngII induces AA formation in obese mice. A: Representative aortas of WT and ob/ob mice infused with saline or AngII for 2 weeks. Scale bar, 5 mm. B: The incidence of AA in AngII-infused WT mice (n = 20) and ob/ob mice (n = 20). AAA, abdominal AA; TAA, thoracic AA; TAAA, thoracoabdominal AA. C: Survival curve of AngII-infused ob/ob mice (n = 20) and WT mice (n = 20). D: Representative images from ultrasonography (top) and quantification (bottom) of maximal aortic diameter after AngII infusion for 14 days. The arrows indicate maximal aortic diameter. E: Histopathological analysis of representative abdominal aortas by H-E staining (top) and quantification of aortic media and adventitia thickness (bottom). Scale bar, 100 μm (top) and 50 µm (bottom) in magnified photographs. The adventitia area is shown with black dotted lines. F: Representative immunofluorescent staining (left) and quantitative analysis (right) of CD68-positive macrophages in abdominal aortas. DAPI indicates the nucleus. Scale bar, 50 μm. N.S. indicates no significant difference. **P < 0.01, ***P < 0.001.

Transcriptome Analysis Reveals That PDGF-D Is Highly Expressed in the PVAT of Obese Mice

To determine whether obesity-induced PVAT dysfunction is involved in the regulation of AA formation and associated with adventitial remodeling in obese mice, we performed gene expression microarray analysis. As indicated in the volcano plots and heatmap, the PVAT cluster showed large overlaps between WT mice, with or without AngII infusion, and the PVAT of ob/ob mice also shared a similar transcriptional profile, with or without AngII treatment. In contrast, there was a great difference in PVAT between WT and ob/ob mice regardless of infusion with saline or AngII (Supplementary Fig. 2A–C). These suggest that obesity, rather than AngII-induced PVAT dysfunction contributes to AA formation in our model. Heatmap and Circos plots showed different expressions in fatty acid metabolism–related, inflammatory response–related, and fibroblast proliferation–related genes (Supplementary Fig. 2C and D). Since AngII-infused ob/ob mice showed significant adventitial hypertrophy and fibroblasts were considered as the main component of the adventitia, we analyzed the transcriptional profile in regulating fibroblast proliferation. Intriguingly, gene pdgfd, which encodes PDGF-D and plays an important role in activating fibroblasts, was highly expressed in the PVAT of ob/ob mice. Next, we examined PDGF-D expression in cells from every layer of the vascular wall, including endothelial cells, smooth muscle cells, adventitial fibroblasts, and adipocytes. The result indicates that PDGF-D is mostly expressed in the adipocyte (Supplementary Fig. 2E). Further, QPCR, immunohistochemistry, and Western blot analysis confirmed the increased expression of PDGF-D in the PVAT of AngII-infused ob/ob mice (Fig. 2A–C) and AngII-infused HFD mice (Fig. 2D–F). According to the phenotype of hypertrophied adventitia in AngII-infused obese mice, we assumed that PDGF-D may be involved in the regulation of adventitia activation and therefore participates in the pathological process of AA formation in obese mice.

Figure 2
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 2

PDGF-D increases in the PVAT of obese mice. A: Relative mRNA expression of pdgfd in aortas and PVAT of AngII-infused WT mice and ob/ob mice. n = 6 each. B: Immunohistochemistry staining of PDGF-D in the abdominal aortas of indicated mice. Scale bar, 50 μm. C: Western blot (top) and quantitative analysis (bottom) of PDGF-D protein expression in PVAT of indicated mice. n = 4 each. D: Relative mRNA expression of pdgfd in aortas and PVAT of AngII-infused low-fat diet (LFD) and HFD mice. n = 6 each. E: Immunohistochemistry staining of PDGF-D in the abdominal aortas of indicated mice. Scale bar, 50 μm. F: Western blot (top) and quantitative analysis (bottom) of PDGF-D protein expression in PVAT of indicated mice. n = 4 each. N.S. indicates no significant difference. **P < 0.01, ***P < 0.001.

Inhibition of PDGF-D Function Reverses AngII-Induced AA in Obese Mice

To verify the effect of PDGF-D on AA formation in obese mice, we treated AngII-infused obese mice with PDGF-D receptor antagonist CP673451. As shown, CP673451 markedly diminished the incidence of AA and improved the survival rate in ob/ob mice after AngII infusion (Fig. 3A–C). PDGF-D has been taken as a fibrosis inducer in many disease models (24,25). In accordance, the thickness and fibrosis of adventitia were remarkably reduced with CP673451 treatment in AngII-infused ob/ob mice (Fig. 3D and E). Moreover, adventitia proliferation and FSP1-positive fibroblast invasion were also decreased with CP673451 treatment (Fig. 3F and G). CP673451 treatment also decreased CD68-positive macrophage infiltration in the adventitia, as well as plasma IL-6 and MCP-1 concentration in AngII-infused ob/ob mice (Fig. 3H and I). Consistently, CP673451 treatment also reduced the incidence of AA and improved the survival rate in AngII-infused HFD mice (Supplementary Fig. 3A–C), accompanied by decreased adventitia fibrosis and inflammation (Supplementary Fig. 3D–G). Together, these suggest that the inhibition of PDGF-D function ameliorates adventitial remodeling–related AA formation in AngII-infused obese mice.

Figure 3
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 3

Inhibition of PDGF-D function ameliorates adventitial remodeling and suppresses AA formation in obese mice. A: Representative aortas of AngII-infused ob/ob mice with CP673451 (CP) or without CP673451 (Ctrl) treatment. Scale bar, 5 mm. B: The incidence of AA in AngII-infused ob/ob mice with CP673451 (n = 8) or without CP673451 (n = 8) treatment. AAA, abdominal AA; TAA, thoracic AA; TAAA, thoracoabdominal AA. C: Survival curve of indicated mice. n = 14 each. D: Histopathological analysis of representative abdominal aortas by H-E staining (top) and quantification of aortic media and adventitia thickness (bottom). Scale bars, 100 μm (top) and 50 µm (bottom) in magnified photographs. Adventitia area is shown with black dotted lines. E: Representative images (top) and quantitative analysis (bottom) of Masson’s trichrome staining of abdominal aortas. Scale bar, 100 μm (top) and 50 µm (bottom) in magnified photographs. F: Representative immunofluorescent staining (top) and quantitative (bottom) analysis of Ki67-positive proliferated cells in abdominal aortas. Scale bar, 50 μm. G: Representative immunofluorescent staining of α-SMA and FSP1 in abdominal aortas (left), and quantitative analysis of FSP1-positive cell invasion into the media of vessel wall (right). The arrows indicate FSP1-positive cell invasion. Scale bar, 50 μm. H: Representative immunofluorescent staining (left) and quantitative analysis (right) of CD68-positive macrophages in abdominal aortas. Scale bar, 50 μm. I: Plasma concentration of IL-6, MCP-1, and tumor necrosis factor-α (TNF-α). n = 8 each. N.S. indicates no significant difference. **P < 0.01, ***P < 0.001.

Adipocyte-Specific PDGF-D Transgenic Mice Is Susceptible to AA Formation After AngII Infusion

To establish a direct link between adipocyte-derived PDGF-D and AA formation, we created PA-Tg mice by using adipocyteprotein-2 promoter (Supplementary Fig. 4A). The mRNA level of pdgfd showed no differences in the aorta, heart, kidney, liver, and lung in PA-Tg mice compared with WT littermates (Supplementary Fig. 4B). In contrast, pdgfd mRNA expression increased clearly in the interscapular brown adipose tissue, subcutaneous white adipose tissue, and PVAT of PA-Tg mice (Supplementary Fig. 4C). The increase of PDGF-D protein in PVAT was also verified by Western blot (Supplementary Fig. 4D). Interestingly, AngII infusion caused a 55% (11 of 20) incidence of AA in PA-Tg mice compared with zero (0 of 20) in WT mice (Fig. 4A and B). Among the 11 occurrences of AA, 6 were abdominal AA and the other 5 were thoracoabdominal AA. Fifteen percent (3 of 20) of PA-Tg mice died as a result of aortic rupture after AngII infusion (Fig. 4C). AngII infusion also resulted in a comparative increase of media thickness in WT and PA-Tg mice, whereas the thickness of adventitia showed a greater increase in AngII-infused PA-Tg mice rather than AngII-infused WT mice. In addition, the adventitia of PA-Tg mice was thicker than WT mice without AngII treatment (Fig. 4D). These results confirm that adipocyte-derived PDGF-D promotes AngII-induced AA formation, including a dramatic adventitial remodeling.

Figure 4
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 4

AngII induces AA formation in adipocyte-specific PA-Tg. A: Representative aortas of WT and PA-Tg mice infused with saline or AngII for 2 weeks. Scale bar, 5 mm. B: The incidence of AA in AngII-infused WT mice (n = 20) and PA-Tg mice (n = 20). AAA, abdominal AA; TAA, thoracic AA; TAAA, thoracoabdominal AA. C: Survival curve of AngII-infused PA-Tg mice (n = 20) and WT mice (n = 20). D: Histopathological analysis of representative abdominal aortas by H-E staining (left) and quantification of aortic media and adventitia thickness (right). Scale bars, 100 μm (top) and 50 µm (bottom) in magnified photographs. Adventitia area is shown with black dotted lines. N.S. indicates no significant difference. ***P < 0.001.

Adventitial Fibrosis and Inflammation Are Involved in AA Formation in AngII-Infused PA-Tg Mice

Accordingly, PA-Tg mice displayed grossly enlarged fibrotic adventitial areas, and AngII infusion amplified the adventitial fibrosis (Fig. 5A). Ki67 staining showed much more proliferated cells in the adventitia of PA-Tg mice than in WT mice (Fig. 5B). In the aneurismal section, we also detected FSP1-positive fibroblast invasion (Fig. 5C). Of note, we detected a significant CD68-positive macrophage infiltration in the adventitia of PA-Tg mice, which was dramatically aggravated after AngII infusion (Fig. 5D). Consistently, the plasma levels of IL-6 and MCP-1 were significantly increased in PA-Tg mice compared with WT mice, and had a much greater increase after AngII infusion (Fig. 5E). These suggest that PDGF-D–mediated adventitial fibrosis and inflammation are involved in AA formation in PA-Tg mice after AngII infusion.

Figure 5
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 5

PDGF-D promotes adventitial fibrosis and inflammation. A: Representative images (left) and quantitative analysis (right) of Masson’s trichrome staining in abdominal aortas of indicated mice. Scale bars, 100 μm (top) and 50 µm (bottom) in magnified photographs. B: Representative immunofluorescent staining (left) and quantitative analysis (right) of Ki67-positive proliferated cells in abdominal aortas. Scale bar, 50 μm. C: Representative immunofluorescent staining of α-SMA and FSP1 in abdominal aortas (left), and quantitative analysis of FSP1-positive cells invasion into the media of vessel wall (right). The arrows indicate FSP1-positive cell invasion. Scale bar, 50 μm. D: Representative immunofluorescent staining (left) and quantitative analysis (right) of CD68-positive macrophages in abdominal aortas. Scale bar, 50 μm. E: Plasma concentration of IL-6 and MCP-1. n = 6 each. *P < 0.05, **P < 0.01, ***P < 0.001.

PDGF-D Activates Adventitial Fibroblasts

To determine the effect of adipocyte-derived PDGF-D on adventitial fibroblasts, we cultured adventitial fibroblasts with WT-CM and PA-Tg-CM. PA-Tg-CM had a threefold increase in PDGF-D concentration compared with WT-CM (Fig. 6D). AngII or PA-Tg-CM, respectively, activated adventitial fibroblast proliferation (Fig. 6A), migration (Fig. 6B), and collagen I expression (Fig. 6C). The combined treatment with PA-Tg-CM and AngII further amplified these effects on adventitial fibroblasts, which indicated the synergistic function of adipocyte-derived PDGF-D and AngII. More importantly, CP673451 inhibited PA-Tg-CM–induced adventitial fibroblast activation, whereas this effect of CP673451 was blunted in AngII-stimulated adventitial fibroblasts. Consistent with the proinflammatory effect in vivo, PA-Tg-CM increased IL-6 and MCP-1 expression in adventitial fibroblasts, and this increase was abolished after CP673451 pretreatment (Fig. 6E). Next, we analyzed the effect of recombinant PDGF-D on cultured adventitial fibroblasts. Likewise, the results confirmed the synergistic function of AngII and recombinant PDGF-D on the regulation of adventitial fibroblast proliferation, migration, collagen expression, and IL-6 and MCP-1 expression (Supplementary Fig. 5A–E). These data indicate that PDGF-D activates adventitial fibroblasts in vitro.

Figure 6
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 6

PDGF-D activates adventitial fibroblasts in vitro. Primary adventitial fibroblasts were cultured with WT-CM or PA-Tg-CM, then stimulated with AngII (10−7 mol/L), treated with CP673451 (300 μmol/L) (CP), or not stimulated or treated (Ctrl). A: Representative images (top) and quantitative analysis (bottom) of EdU proliferation staining of adventitial fibroblasts. Scale bar, 50 μm. n = 6 each. B: Representative images (top) and quantitative analysis (bottom) of transwell migration assay of adventitial fibroblasts. Scale bar, 50 μm. n = 6 each. C: Western blot (top) and quantitative analysis (bottom) of Col1α1 expression in adventitial fibroblasts. n = 4 each. D: ELISA analysis of PDGF-D concentration in WT-CM and PA-Tg-CM. E: QPCR analysis of IL-6/MCP-1 mRNA levels in adventitial fibroblasts. n = 6 each. *P < 0.05, **P < 0.01, ***P < 0.001.

TGF-β Pathway Is Involved in AngII-Induced AA Formation in PA-Tg Mice

Since the TGF-β signaling pathway plays a pivotal role in the regulation of adventitial fibroblast function, as well as AA formation in vivo (26–28), we detected whether PDGF-D stimulated the TGF-β pathway in these mice. First, we found increased TGF-β and downstream collagen I expression in the aortas of PA-Tg mice, and AngII infusion resulted in a further increase (Fig. 7A and B). Consistently, the downstream Smad2/3 phosphorylation was increased in PA-Tg mice, which showed a much higher level after AngII infusion (Fig. 7B). Similarly, recombinant PDGF-D and AngII had a synergistic effect on the TGF-β/Smad signaling pathway in cultured adventitial fibroblasts (Supplementary Fig. 6A). Accordingly, the inhibition of PDGF-D function by CP673451 treatment attenuated the activation of the TGF-β/Smad signaling pathway in AngII-infused ob/ob mice and PA-Tg mice (Supplementary Fig. 6B and C). These suggest that the TGF-β/Smad pathway activation in adventitial fibroblasts is involved in PDGF-D–mediated AA formation during obesity.

Figure 7
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 7

TGF-β and SMAD2/3 pathway is involved in aortas of AngII-infused PA-Tg mice. A: Relative TGF-β and COL1α1 mRNA expression in aortas from saline or AngII-infused WT and PA-Tg mice. n = 6 each. B: Western blot (left) and quantitative analysis (right) of TGF-β, Col1α1, total-SMAD2/3 (T-SMAD2/3), and phosphorylated-SMAD2/3 (P-SMAD2/3) protein expressions in aortas. n = 6 each. *P < 0.05, **P < 0.01, ***P < 0.001.

It is well known that blood pressure elevation contributes to AA formation. Herein we showed that blood pressure had no further elevation in ob/ob mice, HFD mice, and PA-Tg mice after AngII infusion. Meanwhile, CP673451 treatment did not regulate blood pressure in these mice (Supplementary Fig. 7A–C). Therefore, PDGF-D–mediated AA formation was independent of blood pressure regulation. We also detected plasma level of PDGF-D in mice. The results indicated that circulating levels of PDGF-D increased in ob/ob, HFD, and PA-Tg mice, but it is not influenced by AngII or CP673451 treatment (Supplementary Fig. 7D–F). Together, our data illustrate that PVAT-derived PDGF-D contributes to AA formation via adventitial remodeling during obesity (Supplementary Fig. 8).

Discussion

This study mainly reveals that obesity-related PVAT dysfunction contributes to AngII-induced AA formation by secreting PDGF-D, which is identified by transcriptome analysis of PVAT in ob/ob mice. Pharmacological blockade of PDGF-D function successfully reduced AngII-induced AA in obese mice. More importantly, we used PA-Tg mice to confirm the direct role of PDGF-D in AA formation via mediating adventitial fibrosis and inflammation.

Obesity is one of the major causes of morbidity and mortality worldwide, and it is a significant public health burden affecting human beings (1,29,30). The effect of obesity on cardiovascular disease mostly depends on the dysfunction of adipose tissue, especially PVAT (31,32). Herein, we showed that the dysfunction of PVAT contributes to AngII-induced AA in obese mice, which is mediated by PDGF-D–induced adventitial fibrosis and inflammation. PDGF-D is a recently identified member of the PDGF family and participates in the regulation of cardiovascular diseases (33). The PDGF protein family is a potent stimulator for cell proliferation and chemotaxis and is documented to play a major role in cell-cell communication for normal development and pathogenesis (34). Among these proteins, PDGF-D has been well documented to regulate organ fibrosis in different animal models (35). In the cardiovascular system, heart-specific overexpression of PDGF-D induces vascular remodeling, resulting in cardiac fibrosis, dilated cardiomyopathy, and cardiac failure (24). Herein, in addition to promoting adventitial fibrosis, we provided definitive evidence that PDGF-D accelerates adventitial inflammation in obese mice and contributes to AA formation after AngII infusion. Although the mechanism of the differential expression of PDGF-D in lean control and obese mice is unclear, we assumed that the differential expression is a result of the different types of adipocytes (36,37). Chronic inflammation is one of the prime reasons for obesity-related adipose tissue dysfunction, where macrophage activation–mediated inflammatory factor release has been attributed to a central function for fat cell disorders (21,38). Thus, the inhibition of PDGF-D function might be a possible intervention to prevent obesity-related metabolic syndrome.

It is increasingly being accepted that adventitial inflammation plays a key role in the pathogenesis of AA, including infiltration of inflammatory cells in the adventitia and activation of adventitial fibroblasts (39,40). It has been reported that leukocyte-fibroblast interactions in the adventitia potentiate local monocyte recruitment and activation, resulting in AA and aortic dissection (19). Even more, local neutrophil recruitment and activation in adventitia facilitate aortic expansion and lead to aortic rupture eventually (18). Herein we are the first to show a direct link between perivascular adipocytes and adventitial fibroblasts in AA formation. In general, PVAT plays a proinflammatory role in AA development. PVAT-derived proinflammatory factors accelerate the recruitment of macrophages, lymphocytes, and mast cells in the vascular wall (41,42). Although another study (43) revealed that higher thoracic and abdominal aortic dimensions are associated with PVAT volume in a cohort study of 3,001 individuals, supporting the notion that PVAT volume may contribute to aortic remodeling. In our study, a PDGF-D supplement activates primary cultured adventitial fibroblasts and increases the production of IL-6 and MCP-1 in vitro. Accordantly, adipocyte-specific overexpression of PDGF-D in vivo aggravates adventitial fibrosis and inflammation. These indicate a crucial molecular mechanism for adipocyte-derived PDGF-D in adventitial inflammation and AA formation.

Obesity could potentially be an independent risk factor for AA, and meanwhile obesity also has been implicated in the pathogenesis of diabetes. Nevertheless, data from large-scale screenings have shown a paradoxically lower prevalence of AA in patients with diabetes, even those who have been reported as having a negative risk factor for human abdominal AA formation (44). Recently, a report (45) showed that vascular cell division autoantigen 1 (CDA1) plays a role in diabetes to reduce susceptibility to aneurysm. It appears that CDA1 reduces aneurysm severity, but not the onset of aneurysm in this model. A CDA1-mediated TGF-β/Smad pathway may limit the growth of the aneurysm via increasing accumulation of extracellular matrix. On the other hand, our study provides an explanation of how the PDGF-D–induced TGF-β/Smad pathway contributes to the onset of aneurysms via promoting vascular fibrotic response and inflammation during obesity. This explanation is in accordance with the results of a previous study (16) showing that AngII induces abdominal AA in diet-induced obese mice as well as genetic obese mice. It has shown that body weight, but not insulin sensitivity, was a significant predictor of abdominal AA formation in the mouse model (16). Consistently, our results provided experimental evidence for obesity-related AA formation, and a molecular mechanism study proposed that obese fat-derived PDGF-D plays a pivotal role in AA formation. Although epidemic study and basic research have claimed the correlation between obesity and AA, the paradox of obesity and diabetes in AA formation still needs further investigation.

In conclusion, this study shows that obesity-induced PDGF-D in PVAT contributes to AA formation. We illustrate the molecular mechanism that adipocyte-derived PDGF-D promotes adventitial fibrosis and inflammation, which contribute to AA formation during obesity.

Article Information

Acknowledgments. The authors thank Professor Jiqiu Wang (Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai, People’s Republic of China) for providing HFD mice.

Funding. This work was supported by the National Natural Science Foundation of China (grants 91539202, 81570221, 81770495, and 91739303), the Shanghai Municipal Commission of Health and Family Planning (grants 2017YQ076 and 201540222), the Shanghai Sailing Program (grant 17YF1415900), and the China Postdoctoral Science Foundation (grant 2017M621504).

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. Z.-B.Z. and C.-C.R. performed the AngII infusion animal study and wrote the manuscript. J.-R.L. and L.X. performed animal tissue collection and analysis. X.-H.C. carried out ultrasound imaging. Y.-N.D. and M.-X.F. analyzed survival curve data. L.-R.K. and D.-L.Z. performed the primary cell culture. P.-J.G. designed and initiated the experiments. P.-J.G. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Footnotes

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db18-0098/-/DC1.

  • Received January 22, 2018.
  • Accepted May 11, 2018.
  • © 2018 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

References

  1. ↵
    1. Quarta C,
    2. Schneider R,
    3. Tschöp MH
    . Epigenetic ON/OFF switches for obesity. Cell 2016;164:341–342pmid:26824648
    OpenUrlPubMed
    1. Lavie CJ,
    2. Milani RV,
    3. Ventura HO
    . Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol 2009;53:1925–1932pmid:19460605
    OpenUrlFREE Full Text
  2. ↵
    1. Jia G,
    2. Habibi J,
    3. Aroor AR, et al
    . Enhanced endothelium epithelial sodium channel signaling prompts left ventricular diastolic dysfunction in obese female mice. Metabolism 2018;78:69–79pmid:28920862
    OpenUrlPubMed
  3. ↵
    1. Lim S,
    2. Meigs JB
    . Links between ectopic fat and vascular disease in humans. Arterioscler Thromb Vasc Biol 2014;34:1820–1826pmid:25035342
    OpenUrlAbstract/FREE Full Text
    1. Ruan CC,
    2. Ge Q,
    3. Li Y, et al
    . Complement-mediated macrophage polarization in perivascular adipose tissue contributes to vascular injury in deoxycorticosterone acetate-salt mice. Arterioscler Thromb Vasc Biol 2015;35:598–606pmid:25573852
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Sowers JR
    . Endocrine functions of adipose tissue: focus on adiponectin. Clin Cornerstone 2008;9:32–38; discussion 39–40pmid:19046738
    OpenUrlCrossRefPubMed
  5. ↵
    1. Chang L,
    2. Milton H,
    3. Eitzman DT,
    4. Chen YE
    . Paradoxical roles of perivascular adipose tissue in atherosclerosis and hypertension. Circ J 2013;77:11–18pmid:23207957
    OpenUrlCrossRefPubMedWeb of Science
    1. Bussey CE,
    2. Withers SB,
    3. Aldous RG,
    4. Edwards G,
    5. Heagerty AM
    . Obesity-related perivascular adipose tissue damage is reversed by sustained weight loss in the rat. Arterioscler Thromb Vasc Biol 2016;36:1377–1385pmid:27174097
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Chatterjee TK,
    2. Stoll LL,
    3. Denning GM, et al
    . Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ Res 2009;104:541–549pmid:19122178
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Tsai TT,
    2. Nienaber CA,
    3. Eagle KA
    . Acute aortic syndromes. Circulation 2005;112:3802–3813pmid:16344407
    OpenUrlFREE Full Text
  8. ↵
    1. Baxter BT,
    2. Terrin MC,
    3. Dalman RL
    . Medical management of small abdominal aortic aneurysms. Circulation 2008;117:1883–1889pmid:18391122
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Chabok M,
    2. Nicolaides A,
    3. Aslam M, et al
    . Risk factors associated with increased prevalence of abdominal aortic aneurysm in women. Br J Surg 2016;103:1132–1138pmid:27332825
    OpenUrlPubMed
  10. ↵
    1. Chun KC,
    2. Teng KY,
    3. Chavez LA, et al
    . Risk factors associated with the diagnosis of abdominal aortic aneurysm in patients screened at a regional Veterans Affairs health care system. Ann Vasc Surg 2014;28:87–92pmid:24189004
    OpenUrlCrossRefPubMed
  11. ↵
    1. Golledge J,
    2. Clancy P,
    3. Jamrozik K,
    4. Norman PE
    . Obesity, adipokines, and abdominal aortic aneurysm: Health in Men study. Circulation 2007;116:2275–2279pmid:17967974
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Stackelberg O,
    2. Björck M,
    3. Sadr-Azodi O,
    4. Larsson SC,
    5. Orsini N,
    6. Wolk A
    . Obesity and abdominal aortic aneurysm. Br J Surg 2013;100:360–366pmid:23203847
    OpenUrlCrossRefPubMed
  13. ↵
    1. Police SB,
    2. Thatcher SE,
    3. Charnigo R,
    4. Daugherty A,
    5. Cassis LA
    . Obesity promotes inflammation in periaortic adipose tissue and angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol 2009;29:1458–1464pmid:19608970
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Kuivaniemi H,
    2. Platsoucas CD,
    3. Tilson MD III.
    . Aortic aneurysms: an immune disease with a strong genetic component. Circulation 2008;117:242–252pmid:18195185
    OpenUrlFREE Full Text
  15. ↵
    1. Anzai A,
    2. Shimoda M,
    3. Endo J, et al
    . Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture. Circ Res 2015;116:612–623pmid:25563839
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Tieu BC,
    2. Lee C,
    3. Sun H, et al
    . An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. J Clin Invest 2009;119:3637–3651pmid:19920349
    OpenUrlCrossRefPubMedWeb of Science
  17. ↵
    1. Tsuruda T,
    2. Kato J,
    3. Hatakeyama K, et al
    . Adventitial mast cells contribute to pathogenesis in the progression of abdominal aortic aneurysm. Circ Res 2008;102:1368–1377pmid:18451339
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Wang GX,
    2. Cho KW,
    3. Uhm M, et al
    . Otopetrin 1 protects mice from obesity-associated metabolic dysfunction through attenuating adipose tissue inflammation. Diabetes 2014;63:1340–1352pmid:24379350
    OpenUrlAbstract/FREE Full Text
    1. Chistiakov DA,
    2. Grechko AV,
    3. Myasoedova VA,
    4. Melnichenko AA,
    5. Orekhov AN
    . Impact of the cardiovascular system-associated adipose tissue on atherosclerotic pathology. Atherosclerosis 2017;263:361–368pmid:28629772
    OpenUrlPubMed
  19. ↵
    1. Zhao H,
    2. Shang Q,
    3. Pan Z, et al
    . Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissues. Diabetes 2018;67:235–247
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Pontén A,
    2. Folestad EB,
    3. Pietras K,
    4. Eriksson U
    . Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice. Circ Res 2005;97:1036–1045pmid:16224065
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Andrae J,
    2. Gallini R,
    3. Betsholtz C
    . Role of platelet-derived growth factors in physiology and medicine. Genes Dev 2008;22:1276–1312pmid:18483217
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Wheeler JB,
    2. Ikonomidis JS,
    3. Jones JA
    . Connective tissue disorders and cardiovascular complications: the indomitable role of transforming growth factor-beta signaling. Adv Exp Med Biol 2014;802:107–127pmid:24443024
    OpenUrlCrossRefPubMed
    1. Gallo EM,
    2. Loch DC,
    3. Habashi JP, et al
    . Angiotensin II-dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis. J Clin Invest 2014;124:448–460pmid:24355923
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    1. Tojais NF,
    2. Cao A,
    3. Lai YJ, et al
    . Codependence of bone morphogenetic protein receptor 2 and transforming growth factor-β in elastic fiber assembly and its perturbation in pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2017;37:1559–1569pmid:28619995
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Jensen MD,
    2. Ryan DH,
    3. Apovian CM, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society
    . 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society [published correction appears in J Am Coll Cardiol 2014;63:3029–3030]. J Am Coll Cardiol 2014;63:2985–3023pmid:24239920
    OpenUrlFREE Full Text
  25. ↵
    1. Meng Z-X,
    2. Wang L,
    3. Xiao Y,
    4. Lin JD
    . The Baf60c/Deptor pathway links skeletal muscle inflammation to glucose homeostasis in obesity. Diabetes 2014;63:1533–1545pmid:24458360
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Szasz T,
    2. Bomfim GF,
    3. Webb RC
    . The influence of perivascular adipose tissue on vascular homeostasis. Vasc Health Risk Manag 2013;9:105–116pmid:23576873
    OpenUrlPubMed
  27. ↵
    1. Rosei CA,
    2. Withers SB,
    3. Belcaid L,
    4. De Ciuceis C,
    5. Rizzoni D,
    6. Heagerty AM
    . Blockade of the renin-angiotensin system in small arteries and anticontractile function of perivascular adipose tissue. J Hypertens 2015;33:1039–1045pmid:25909701
    OpenUrlCrossRefPubMed
  28. ↵
    1. Bergsten E,
    2. Uutela M,
    3. Li X, et al
    . PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat Cell Biol 2001;3:512–516pmid:11331881
    OpenUrlCrossRefPubMedWeb of Science
  29. ↵
    1. Onogi Y,
    2. Wada T,
    3. Kamiya C, et al
    . PDGFRβ regulates adipose tissue expansion and glucose metabolism via vascular remodeling in diet-induced obesity. Diabetes 2017;66:1008–1021pmid:28122789
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Huang J,
    2. Beyer C,
    3. Palumbo-Zerr K, et al
    . Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann Rheum Dis 2016;75:883–890pmid:25858641
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Chang L,
    2. Garcia-Barrio MT,
    3. Chen YE
    . Brown adipose tissue, not just a heater. Arterioscler Thromb Vasc Biol 2017;37:389–391pmid:28228444
    OpenUrlFREE Full Text
  32. ↵
    1. Wang GX,
    2. Zhao XY,
    3. Lin JD
    . The brown fat secretome: metabolic functions beyond thermogenesis. Trends Endocrinol Metab 2015;26:231–237pmid:25843910
    OpenUrlCrossRefPubMed
  33. ↵
    1. Withers SB,
    2. Agabiti-Rosei C,
    3. Livingstone DM, et al
    . Macrophage activation is responsible for loss of anticontractile function in inflamed perivascular fat. Arterioscler Thromb Vasc Biol 2011;31:908–913pmid:21273560
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Nahrendorf M,
    2. Keliher E,
    3. Marinelli B, et al
    . Detection of macrophages in aortic aneurysms by nanoparticle positron emission tomography-computed tomography. Arterioscler Thromb Vasc Biol 2011;31:750–757pmid:21252070
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Liu Z,
    2. Luo H,
    3. Zhang L, et al
    . Hyperhomocysteinemia exaggerates adventitial inflammation and angiotensin II-induced abdominal aortic aneurysm in mice. Circ Res 2012;111:1261–1273pmid:22912384
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Lee HY,
    2. Després JP,
    3. Koh KK
    . Perivascular adipose tissue in the pathogenesis of cardiovascular disease. Atherosclerosis 2013;230:177–184pmid:24075741
    OpenUrlCrossRefPubMedWeb of Science
  37. ↵
    1. Sakaue T,
    2. Suzuki J,
    3. Hamaguchi M, et al
    . Perivascular adipose tissue angiotensin II type 1 receptor promotes vascular inflammation and aneurysm formation. Hypertension 2017;70:780–789pmid:28760942
    OpenUrlPubMed
  38. ↵
    1. Thanassoulis G,
    2. Massaro JM,
    3. Corsini E, et al
    . Periaortic adipose tissue and aortic dimensions in the Framingham Heart Study. J Am Heart Assoc 2012;1:e000885pmid:23316310
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Kent KC,
    2. Zwolak RM,
    3. Egorova NN, et al
    . Analysis of risk factors for abdominal aortic aneurysm in a cohort of more than 3 million individuals. J Vasc Surg 2010;52:539–548pmid:20630687
    OpenUrlCrossRefPubMedWeb of Science
  40. ↵
    1. Li J,
    2. Huynh P,
    3. Dai A, et al
    . Diabetes reduces severity of aortic aneurysms depending on the presence of cell division autoantigen 1 (CDA1). Diabetes 2018;67:755–768
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top
Diabetes: 67 (8)

In this Issue

August 2018, 67(8)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by Author
  • Masthead (PDF)
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Perivascular Adipose Tissue–Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity
(Your Name) has forwarded a page to you from Diabetes
(Your Name) thought you would like to see this page from the Diabetes web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Perivascular Adipose Tissue–Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity
Ze-Bei Zhang, Cheng-Chao Ruan, Jing-Rong Lin, Lian Xu, Xiao-Hui Chen, Ya-Nan Du, Meng-Xia Fu, Ling-Ran Kong, Ding-Liang Zhu, Ping-Jin Gao
Diabetes Aug 2018, 67 (8) 1549-1560; DOI: 10.2337/db18-0098

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Perivascular Adipose Tissue–Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity
Ze-Bei Zhang, Cheng-Chao Ruan, Jing-Rong Lin, Lian Xu, Xiao-Hui Chen, Ya-Nan Du, Meng-Xia Fu, Ling-Ran Kong, Ding-Liang Zhu, Ping-Jin Gao
Diabetes Aug 2018, 67 (8) 1549-1560; DOI: 10.2337/db18-0098
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Research Design and Methods
    • Results
    • Discussion
    • Article Information
    • Footnotes
    • References
  • Figures & Tables
  • Suppl Material
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Deficiency of Stat1 in CD11c+ Cells Alters Adipose Tissue Inflammation and Improves Metabolic Dysfunctions in Mice Fed a High-Fat Diet
  • Placental Insulin/IGF-1 Signaling, PGC-1α, and Inflammatory Pathways Are Associated With Metabolic Outcomes at 4–6 Years of Age: The ECHO Healthy Start Cohort
  • Defective FXR-SHP Regulation in Obesity Aberrantly Increases miR-802 Expression, Promoting Insulin Resistance and Fatty Liver
Show more Obesity Studies

Similar Articles

Navigate

  • Current Issue
  • Online Ahead of Print
  • Scientific Sessions Abstracts
  • Collections
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes Care
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X.