Adipose Tissue Angiogenesis Research Articles

Interaction between adipocytes and macrophages participates in chick subcutaneous adipose tissue angiogenesis under cold stress conditions

Previous studies have shown that subcutaneous adipose tissue is an important energy supply organ for chicks before and after birth, except yolk. So far, the significance of large deposits of subcutaneous adipose tissue in chicks is unclear. Therefore, this study takes the information interaction between adipocytes and macrophages as the starting point to explore whether adipocytes and macrophages could participate in adipose tissue fibrosis, angiogenesis, adaptive thermogenesis and other related functions in a specific metabolic environment. Under cold stress, the expression levels of genes related to lipidolysis, lipid transport and fatty acid oxidation in adipose tissue of chicks were significantly increased, but the expression levels of genes related to mitochondrial uncoupling were not significantly changed. Through Masson staining of adipose tissue of chicks under cold stress, it was found that the level of vascularization in adipose tissue of chicks was significantly increased. We found that the interaction between adipocyte and macrophage could participate in the angiogenesis related process of adipocytes in chicks through the HIF1A–VEGFA pathway. The analysis of lipid metabolism in subcutaneous adipose tissue of chicks from the perspective of cell heterogeneity will expand the understanding of lipid metabolism in chicks and provide a theoretical basis for chick rearing.

MiR-221-3p/222-3p Cluster Expression in Human Adipose Tissue Is Related to Obesity and Type 2 Diabetes.

The progression of obesity and type 2 diabetes (T2D) is intricately linked with adipose tissue (AT) angiogenesis. Despite an established network of microRNAs (miRNAs) regulating AT function, the specific role of angiogenic miRNAs remains less understood. The miR-221/222 cluster has recently emerged as being associated with antiangiogenic activity. However, no studies have explored its role in human AT amidst the concurrent development of obesity and T2D. Therefore, this study aims to investigate the association between the miR-221-3p/222-3p cluster in human AT and its regulatory network with obesity and T2D. MiR-221-3p/222-3p and their target gene (TG) expression levels were quantified through qPCR in visceral (VAT) and subcutaneous (SAT) AT from patients (n = 33) categorized based on BMI as normoweight (NW) and obese (OB) and by glycemic status as normoglycemic (NG) and type 2 diabetic (T2D) subjects. In silico analyses of miR-221-3p/222-3p and their TGs were conducted to identify pertinent signaling pathways. The results of a multivariate analysis, considering the simultaneous expression of miR-221-3p and miR-222-3p as dependent variables, revealed statistically significant distinctions when accounting for variables such as tissue depot, obesity, sex, and T2D as independent factors. Furthermore, both miRNAs and their TGs exhibited differential expression patterns based on obesity severity, glycemic status, sex, and type of AT depot. Our in silico analysis indicated that miR-221-3p/222-3p cluster TGs predominantly participate in angiogenesis, WNT signaling, and apoptosis pathways. In conclusion, these findings underscore a promising avenue for future research, emphasizing the miR-221-3p/222-3p cluster and its associated regulatory networks as potential targets for addressing obesity and related metabolic disorders.

MiR-379-3p inhibits fat grafting survival and angiogenesis by targeting SOCS1-mediated adipose inflammation

BackgroundThis research probed the relevant mechanism of miR-379-3p by regulating suppressor of cytokine signaling1 (SOCS1) in the processes of inflammation, oxidative stress, and angiogenesis in fat grafting. An increasing body of research indicates the involvement of miRNA/mRNA pathways in the process of fat transplantation, yet the underlying molecular mechanisms remain to be fully elucidated. ResultsmiR-379-3p knockdown improved the survival rate of adipocytes, promoted adipose tissue angiogenesis, and reduced inflammation and oxidative stress levels. miR-379-3p targeted SOCS1. SOCS1 upregulation improved adipose tissue survival and angiogenesis and reduced inflammation. miR-379-3p affected adipose tissue survival, angiogenesis, and inflammation by targeting SOCS1 expression. ConclusionsmiR-379-3p inhibits fat grafting survival and angiogenesis by targeting SOCS1 to mediate adipose inflammation, suffering a novel way to improve fat grafting technique development.How to cite: Zhu J, Zhao F, Han X, et al. miR-379-3p inhibits fat grafting survival and angiogenesis by targeting SOCS1-mediated adipose inflammation. Electron J Biotechnol 2024:67. https://doi.org/10.1016/j.ejbt.2023.11.001.

Short term effect of tetrahydrocurcumin on adipose angiogenesis in very high-fat diet-induced obesity mouse model.

Tetrahydrocurcumin (THC) has been shown to possess anti-angiogenic activities. This study aims to investigate the effects of THC on adipose angiogenesis and expression of angiogenic factors that occurs in 60% high-fat diet-induced obese mice. Male ICR mice were randomly divided into 3 groups: mice fed with a low-fat diet (LFD group); mice fed with very high fat diet (VHFD group), and mice fed with VHFD supplemented with THC (300 mg/kg/day orally) (VHFD+THC treated group) for 6 weeks. Body weight (BW), food intake, fasting blood sugar (FBS), lipid profiles and visceral fats weight (VF) were measured. The microvascular density (MVD), TNF-α, VEGF, MMP-2, and MMP-9 expressions were evaluated. The VHFD group had significantly increased total cholesterol, triglyceride, food intake, BW, VF, VF/BW ratio, adipocyte size and the number of crown-liked structures as compared to LFD group. THC supplementation markedly reduced these parameters and adipocyte hypertrophy and inflammation in white adipose tissues. MVD, TNF-α, VEGF, MMP-2, and MMP-9 were over-expressed in the VHFD group. However, THC supplementation decreased MVD and reduced expression of TNF-α, VEGF, MMP-2, and MMP-9. In conclusion, THC suppressed angiogenesis in adipose tissue by the downregulation of TNF-α, VEGF, MMP-2, and MMP-9. With its effects on lipid metabolism as well as on food consumption, THC could contribute to lower visceral fat and body weight. Overall, our study demonstrated the potential benefit of THC in mitigating obesity and associated metabolic disorders along with elucidated the suppression of adipose angiogenesis as one of its underlying mechanisms.

THU204 Serum Vascular Endothelial Growth Factor-A Levels According To Pubertal State And Body Weight In Children

Abstract Disclosure: H. Nam: Grant Recipient; Self; Supported by a Korea University Grant. E. Kang: None. Y. Rhie: None. K. Lee: None. Objectives: Childhood obesity may lead to early puberty in girls, however, it remains unclear whether early thelarche in overweight girls is related to central activation of the gonadotropin releasing hormone-gonadotropin axis. Vascular endothelial growth factor-A (VEGF-A) is essential for governing angiogenesis in adipose tissue. We assessed serum VEGF-A level according to pubertal state and weight in girls. Patients and Methods: Total 165 girls were classified as prepuberty (n=40), puberty with peak LH <5.0 IU/L (n=60), and puberty with peak LH ≥5.0 IU/L (n=65). Serum VEGF-A, sex hormone, gonadotropin level and bone age were analyzed according to pubertal state and overweight including obesity. We measured serum level of VEGF-A using ELISA kit. Results: Their chronological age were similar (7.8±1.2, 7.9±0.8, and 8.0±0.9 years, p=0.410 in prepuberty, puberty with peak LH <5.0 IU/L, puberty with peak LH ≥5.0 IU/L, respectively). The mean VEGF-A level was higher in puberty girls (399.3±206.2, 633.5±473.0, 605.7±392.4 pg/mL, P=0.009) and was significantly correlated with Tanner stage (r=0.224, p=0.004), BMI SDS (r=0.191, p=0.014), and weight SDS (r=0.202, p=0.009). When sub-analysis with the degree of obesity, VEGF-A level (802.2±556.0 pg/mL) was highest in overweight puberty girls with peak LH <5 IU/L and was significantly correlated with peak LH (r=0.397, p=0.044) and peak LH/FSH (r=0.409, p=0.038). Conclusions: Our study showed higher VEGF-A levels in overweight puberty girls. Obesity-associated VEGF-A rise may involve in the progression of precocious puberty. Further studies related to pathophysiological mechanism are needed. Presentation: Thursday, June 15, 2023

Inhibition of adipose tissue angiogenesis prevents rebound weight gain after caloric restriction in mice fed a high-fat diet

AimsWe investigated whether modulation of white adipose tissue (WAT) vasculature regulates rebound weight gain (RWG) after caloric restriction (CR) in mice fed a high-fat diet (HFD). Main methodsWe compared changes in energy balance, hypothalamic neuropeptide gene expression, and characteristics of WAT by RT-qPCR, ELISA, immunohistochemistry, and adipose-derived stromal vascular fraction spheroid sprouting assay in obese mice fed a HFD ad libitum (HFD-AL), mice under 40 % CR for 3 or 4 weeks, mice fed HFD-AL for 3 days after CR (CRAL), and CRAL mice treated with TNP-470, an angiogenic inhibitor. Key findingsWAT angiogenic genes were expressed at low levels, but WAT vascular density was maintained in the CR group compared to that in the HFD-AL group. The CRAL group showed RWG, fat regain, and hyperphagia with higher expression of angiogenic genes and reduced pericyte coverage of the endothelium in WAT on day 3 after CR compared to the CR group, indicating rapidly increased angiogenic activity after CR. Administration of TNP-470 suppressed RWG, fat regain, and hyperphagia only after CR compared to the CRAL group. Changes in circulating leptin levels and hypothalamic neuropeptide gene expression were correlated with changes in weight and fat mass, suggesting that TNP-470 suppressed hyperphagia independently of the hypothalamic melanocortin system. Additionally, TNP-470 increased gene expression related to thermogenesis, fuel utilization, and browning in brown adipose tissue (BAT) and WAT, indicating TNP-470-induced increase in thermogenesis. SignificanceModulation of the WAT vasculature attenuates RWG after CR by suppressing hyperphagia and increasing BAT thermogenesis and WAT browning.

WED-403 - Perivascular macrophages contribute to adipose tissue angiogenesis in patients with advanced non-alcoholic fatty liver disease

WED-403 - Perivascular macrophages contribute to adipose tissue angiogenesis in patients with advanced non-alcoholic fatty liver disease

Adipose tissue angiogenesis genes are down-regulated by grape polyphenols supplementation during a human overfeeding trial

The adaptive response to overfeeding is associated with profound modifications of gene expression in adipose tissue to support lipid storage and weight gain. The objective of this study was to assess in healthy lean men whether a supplementation with polyphenols could interact with these molecular adaptations. Abdominal subcutaneous adipose tissue biopsies were sampled from 42 subjects participating to an overfeeding protocol providing an excess of 50% of their total energy expenditure for 31 days, and who were supplemented with 2 g/day of grape polyphenols or a placebo. Gene expression profiling was performed by RNA sequencing.Overfeeding led to a modification of the expression of 163 and 352 genes in the placebo and polyphenol groups, respectively. The GO functions of these genes were mostly involved in lipid metabolism, followed by genes involved in adipose tissue remodeling and expansion. In response to overfeeding, 812 genes were differentially regulated between groups. Among them, a set of 41 genes were related to angiogenesis and were down-regulated in the polyphenol group. Immunohistochemistry targeting PECAM1, as endothelial cell marker, confirmed reduced angiogenesis in this group. Finally, quercetin and isorhamnetin, two polyphenol species enriched in the plasma of the volunteers submitted to the polyphenols, were found to inhibit human umbilical vein endothelial cells migration in vitro.Polyphenol supplementation do not prevent the regulation of genes related to lipid metabolism in human adipose tissue during overfeeding, but impact the angiogenesis pathways. This may potentially contribute to a protection against adipose tissue expansion during dynamic phase of weight gain.

Inflammatory biomarkers, angiogenesis and lymphangiogenesis in epicardial adipose tissue correlate with coronary artery disease

In this study, we explored the relationship between inflammatory adipokine levels and coronary artery disease (CAD). We collected subcutaneous adipose tissues(SAT), pericardial adipose tissues(PAT), and epicardial adipose tissues (EAT) and serum samples from 26 inpatients with CAD undergone coronary artery bypass grafting and 20 control inpatients without CAD. Serum inflammatory adipokines were measured by ELISA. Quantitative real-time PCR and western blot were used to measure gene and protein expression. Adipocyte morphology was assessed by H&E staining. Immunohistochemistry and immunofluorescence were used to measure endothelial and inflammatory markers. Serum pro- and anti-inflammatory adipokine levels were higher and lower, respectively, in the CAD group than those in the control group (P < 0.05). In CAD, the pro-inflammatory adipokine levels via ELISA in EAT and PAT were elevated. Pro-inflammatory adipokine mRNA expression was increased, while anti-inflammatory adipokine mRNA expression decreased, in CAD relative to NCAD in EAT and PAT rather than SAT. In EAT, adipocyte area and macrophage-specific staining were lower, while lymphatic vessel marker expression was higher in CAD. Additionally, the endothelial marker expression in EAT was higher than PAT in CAD. The three tissue types had different blood vessel amounts in CAD. The regulation and imbalance expression of the novel biomarkers, including inflammatory adipokine, macrophage infiltration, angiogenesis, and lymphangiogenesis in EAT and PAT, may be related to the pathogenesis of CAD. The serum levels of inflammatory adipokines may correlate to CAD, which requires large sample size studies to get further validation before clinic practice.

Liraglutide promotes angiogenesis in adipose tissue via suppression of adipocyte-derived IL-6

Accumulating evidence suggests that Liraglutide is a favorable treatment for obese people. Obesity induces cellular senescence and accumulated senescent adipocytes in adipose tissue. However, the role of Liraglutide in adipose tissue (AT) senescence and the underlying mechanisms remain obscure. In this study, we found that HFD induces adipocyte senescence and impaired angiogenesis in AT. The deleterious effects provoked unhealthy adipose tissue remodeling and metabolic disturbance. In contrast, treatment of Liraglutide promoted weight reduction, alleviated adipose tissue senescence, and improved angiogenesis in AT. Notably, we demonstrated that Liraglutide promotes angiogenesis in AT dependent on adipocyte-derived IL-6. These findings revealed distinctive roles of Liraglutide in the regulation of adipocyte senescence and provide a therapeutic potential to obesity-associated metabolic disorders.

Regulatory Effects of Curcumin on Platelets: An Update and Future Directions.

The rhizomatous plant turmeric, which is frequently used as a spice and coloring ingredient, yields curcumin, a bioactive compound. Curcumin inhibits platelet activation and aggregation and improves platelet count. Platelets dysfunction results in several disorders, including inflammation, atherothrombosis, and thromboembolism. Several studies have proved the beneficial role of curcumin on platelets and hence proved it is an important candidate for the treatment of the aforementioned diseases. Moreover, curcumin is also frequently employed as an anti-inflammatory agent in conventional medicine. In arthritic patients, it has been shown to reduce the generation of pro-inflammatory eicosanoids and to reduce edema, morning stiffness, and other symptoms. Curcumin taken orally also reduced rats' acute inflammation brought on by carrageenan. Curcumin has also been proven to prevent atherosclerosis and platelet aggregation, as well as to reduce angiogenesis in adipose tissue. In the cerebral microcirculation, curcumin significantly lowered platelet and leukocyte adhesion. It largely modulated the endothelium to reduce platelet adhesion. Additionally, P-selectin expression and mice survival after cecal ligation and puncture were improved by curcumin, which also altered platelet and leukocyte adhesion and blood-brain barrier dysfunction. Through regulating many processes involved in platelet aggregation, curcuminoids collectively demonstrated detectable antiplatelet activity. Curcuminoids may therefore be able to prevent disorders linked to platelet activation as possible therapeutic agents. This review article proposes to highlight and discuss the regulatory effects of curcumin on platelets.

Single-cell transcriptomics reveals an angiogenic cell population for therapeutic angiogenesis in adipose tissue

Abstract Background Therapeutic angiogenesis mediated by stem/progenitor cells is an attractive therapeutic option against cardiovascular disease (CVD). Adipose tissue (AT) can be safely obtained even in CVD patients with anti-platelet medications, and it is a readily available source of culture-expanded adipose-derived stem cells (ADSCs) for transplantation. Single-cell transcriptome enables us to screen all the surface markers at once, while conventional strategies have been limited for the number of target markers. Furthermore, gene profiling at single-cell resolution can be used for the quantification of each marker by how many favorable cells can be purified without mixing of detrimental cells. Purpose We aimed to identify and characterize a cell population with in vivo angiogenic potential by single-cell RNA sequencing (scRNA-seq) analysis and xenograft experiments. Methods We revisited scRNA-seq datasets of single cell fraction from AT, bone-marrow (BM), and umbilical-cord blood (UCB, n=6/organ) to find cell populations with pro-angiogenic potential. Next, we collected AT from CVD patients (n=23) and used multicolor flow cytometry to quantify and sort the specific populations. PBS, the specific marker-negative and unsorted ADSCs were used as controls. Xenograft models of PKH26 pre-labeled human ADSC transplantation in limb ischemia were used to evaluate the lectin capillary density, PKH+ engrafted ADSCs, and blood flow recovery. Results Clustering divided CD45–CD31–CD34+ progenitor fraction into 3 clusters. We identified pro-/anti-angiogenic clusters based on the expressions of well-known pro-/anti-angiogenic factors. All genes encoding cell-surface proteins were compared in this functional clustering, resulted in 17 markers screened (Fig. 1A, B). Taken together with enrichment analysis, CD271+ cells showed predominant and pro-angiogenic gene profile from the other top candidates including CD36 and CD54 (Fig. 1C, D). Next, we evaluated the number and gene profile of CD271+ cells in well-known stem cell sources including BM and UCB. Surprisingly, the number of CD271 expressing cells were significantly lower and did not show angiogenic gene profile in BM and UCB (Fig. 2A). In analysis of AT from 23 CVD patients, CD271+ cells were significantly decreased by donor insulin resistance (Fig. 2B). Cell therapy using CD271+ ADSCs demonstrated in vivo angiogenic capacity compared to those of CD271– ADSCs and PBS in limb ischemia model. Furthermore, CD271+ ADSC transplantation showed enhanced efficacy compared to unsorted ADSCs from the same donors (Fig. 2C–E). Conclusion In this study, we identified CD271+ cell population in AT as an angiogenic cell population through scRNA-seq analysis and cell therapy experiments. AT obtained from donors without insulin resistance would be the most suitable for CD271+ ADSC isolation. CD271+ ADSC transplantation with a promising angiogenic capacity could contribute better cell-based therapy tackling CVD. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Japan Society for the Promotion of Science (JSPS) KAKENHI (Tokyo, Japan)

Comparison of eight weeks of resistance training and high-intensity intermittent aerobic training on the expression of microRNAs associated with adipose tissue angiogenesis and antiangiogenesis in rats fed a high-fat diet

زمینه و هدف: فعالیت‌های ورزشی و چاقی، رگ‌زایی در بافت چربی را تغییر می‌دهند و در نتیجه تغییرات زیادی در فرایندهای متابولیکی ایجاد می‌کنند. هدف از این پژوهش مقایسة تأثیر هشت هفته تمرین مقاومتی و تناوبی هوازی با شدت بالا بر بیان miRNAهای مرتبط با رگ‌زایی و ضدرگ‌زایی بافت چربی در موش‌های صحرایی تغذیه‌شده با رژیم غذایی پرچرب بود.مواد و روش‌ها: در پژوهش بنیادی و تجربی حاضر، 60 سر موش صحرایی نر ویستار شش‌هفته‌ای ( g35/11 ± 40/192 = میانگین وزن بدن) از انستیتو پاستور ایران تهیه شد. حیوانات پس از انتقال به محیط آزمایشگاه و یک هفته آشنایی با محیط جدید، به‌طور تصادفی به شش گروه مساوی تقسیم شدند: 1. غذای عادی (CO)، 2. غذای عادی+ تمرین مقاومتی (NRT)، 3. غذای عادی+ تمرین تناوبی (NHT)، 4. غذای پرچرب (HF)، 5. غذای پرچرب+تمرین مقاومتی (HFRT)، 6. غذای پرچرب+ تمرین تناوبی(HFHT) n= 10) در هر گروه). گروه‌های تمرینی به مدت هشت هفته و هر هفته پنج جلسه قرارداد تمرینی خود را اجرا کردند. تمرین مقاومتی شامل صعود از نردبان یک‌متری با شیب 90 درجه و 46 پله بود؛ در ابتدا وزنة بسته‌شده به دم موش‌ها 30 درصد وزن بدن آن‌ها بود و به‌تدریج به حدود 180 درصد وزن بدن آن‌ها در هفتة پایانی رسید. تمرینات در پنج نوبت چهار تکراری اجرا شد. تمرین تناوبی هوازی با شدت بالا روی نوار گردان با سرعت اولیة ۱۵ متر در دقیقه شروع شد و در هر جلسه، یک تا دو متر در دقیقه، براساس توانایی موش‌ها به سرعت نوار گردان اضافه شد. در هفتة پایانی، تمرین به شش وهلة سه‌دقیقه‌ای دویدن با سرعت ۴۰ متر بر دقیقه با شیب 15 درجه رسید. به‌منظور بررسی تأثیر تمرینات مقاومتی و تناوبی هوازی و رژیم غذایی پرچرب (58 درصد کالری به شکل چربی) بر متغیرهای miR-221, miR-222, miR-329 و VEGF، آزمودنی‌ها در هر گروه 48 ساعت پس از آخرین جلسة تمرینی کشته شدند و نمونه‌برداری از بافت چربی مزنتریک (روده بند) بلافاصله پس از کشتن حیوانات با دقت انجام گرفت. تجزیه‌وتحلیل داده‌ها با استفاده از آزمون‌های t مستقل و آنوای یک و دوراهه در سطح معناداری 05/0 ≥P انجام گرفت.نتایج: نتایج نشان داد در miR-221 ,miR-222 و VEGF در گروه‌های غذای عادی+ تمرین مقاومتی ، غذای عادی+ تمرین تناوبی و غذای پرچرب+ تمرین مقاومتی نسبت به گروه کنترل به‌طور معناداری بیشتر بود (01/0≥P). اما miR-329 فقط در گروه غذای پرچرب به‌طور معناداری بیشتر از گروه غذای عادی+ تمرین تناوبی بود (022/0=P).نتیجه‌گیری: به‌طور کلی نتایج پژوهش حاضر نشان داد تمرینات مقاومتی و تناوبی هوازی با شدت بالا از طریق افزایش miR-221, miR-222 و کاهش miR329 به فعال شدن مسیرهایی که سبب افزایش پروتئین VEGF می‌شوند و در نهایت افزایش رگ‌زایی در موش‌هایی با رژیم غذایی پرچرب و عادی منجر شد. ازاین‌رو این تمرینات عامل مهم رگ‌زایی و سازوکاری در بافت چربی هستند که ممکن است طی این فرایند بتوانند تغییرات زیادی را در بافت چربی ایجاد کنند. هرچند به‌منظور تأیید این نکته و تعمیم آن به انسان به پژوهش‌های بیشتر به‌ویژه بر نمونه‌های انسانی نیاز است. همچنین با توجه به اینکه تأثیر تمرین مقاومتی بر miRNAها نسبت به تمرین تناوبی بیشتر بود، این تمرینات می‌تواند جایگزین مناسبی برای تمرینات تناوبی باشد.

Depot- and diabetes-specific differences in norepinephrine-mediated adipose tissue angiogenesis, vascular tone, collagen deposition and morphology in obesity

AimsNorepinephrine (NE) is a known regulator of adipose tissue (AT) metabolism, angiogenesis, vasoconstriction and fibrosis. This may be through autocrine/paracrine effects on local resistance vessel function and morphology. The aims of this study were to investigate, in human subcutaneous and omental adipose tissue (SAT and OAT): NE synthesis, angiogenesis, NE-mediated arteriolar vasoconstriction, the induction of collagen gene expression and its deposition in non-diabetic versus diabetic obese subjects. Materials and methodsSAT and OAT from obese patients were used to investigate tissue NE content, tyrosine hydroxylase (TH) density, angiogenesis including capillary density, angiogenic capacity and angiogenic gene expression, NE-mediated arteriolar vasoconstriction and collagen deposition. Key findingsIn the non-diabetic group, NE concentration, TH immunoreactivity, angiogenesis and maximal vasoconstriction were significantly higher in OAT compared to SAT (p < 0.05). However, arterioles from OAT showed lower NE sensitivity compared to SAT (10−8 M to 10–7.5 M, p < 0.05). A depot-specific difference in collagen deposition was also observed, being greater in OAT than SAT. In the diabetic group, no significant depot-specific differences were seen in NE synthesis, angiogenesis, vasoconstriction or collagen deposition. SAT arterioles showed significantly lower sensitivity to NE (10−8 M to 10–7.5 M, p < 0.05) compared to the non-diabetic group. SignificanceSAT depot in non-diabetic obese patients exhibited relatively low NE synthesis, angiogenesis, tissue fibrosis and high vasoreactivity, due to preserved NE sensitivity. The local NE synthesis in OAT and diabetes desensitizes NE-induced vasoconstriction, and may also explain the greater tissue angiogenesis and fibrosis in these depots.

Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice.

Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in obesity leads to a state of low-grade chronic inflammation and dysregulated metabolism, resulting in insulin resistance and metabolic syndrome. Adipose tissue macrophages (ATMs) accumulate in obesity and are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. Macrophages are rich sources of cyclooxygenase (COX), the rate limiting enzyme for prostaglandin E2 (PGE2) production. When mice were fed a high-fat diet (HFD), ATMs increased expression of COX-2. Selective myeloid cell COX-2 deletion resulted in increased monocyte recruitment and proliferation of ATMs, leading to increased proinflammatory ATMs with decreased phagocytic ability. There were increased weight gain and adiposity, decreased peripheral insulin sensitivity and glucose utilization, increased adipose tissue inflammation and fibrosis, and abnormal adipose tissue angiogenesis. HFD pair-feeding led to similar increases in body weight, but mice with selective myeloid cell COX-2 still exhibited decreased peripheral insulin sensitivity and glucose utilization. Selective myeloid deletion of the macrophage PGE2 receptor subtype, EP4, produced a similar phenotype, and a selective EP4 agonist ameliorated the metabolic abnormalities seen with ATM COX-2 deletion. Therefore, these studies demonstrated that an ATM COX-2/PGE2/EP4 axis plays an important role in inhibiting adipose tissue dysfunction.

Healthy versus Unhealthy Adipose Tissue Expansion: the Role of Exercise.

Although the hallmark of obesity is the expansion of adipose tissue, not all adipose tissue expansion is the same. Expansion of healthy adipose tissue is accompanied by adequate capillary angiogenesis and mitochondria-centered metabolic integrity, whereas expansion of unhealthy adipose tissue is associated with capillary and mitochondrial derangement, resulting in deposition of immune cells (M1-stage macrophages) and excess production of pro-inflammatory cytokines. Accumulation of these dysfunctional adipose tissues has been linked to the development of obesity comorbidities, such as type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease, which are leading causes of human mortality and morbidity in modern society. Mechanistically, vascular rarefaction and mitochondrial incompetency (for example, low mitochondrial content, fragmented mitochondria, defective mitochondrial respiratory function, and excess production of mitochondrial reactive oxygen species) are frequently observed in adipose tissue of obese patients. Recent studies have demonstrated that exercise is a potent behavioral intervention for preventing and reducing obesity and other metabolic diseases. However, our understanding of potential cellular mechanisms of exercise, which promote healthy adipose tissue expansion, is at the beginning stage. In this review, we hypothesize that exercise can induce unique physiological stimuli that can alter angiogenesis and mitochondrial remodeling in adipose tissues and ultimately promote the development and progression of healthy adipogenesis. We summarize recent reports on how regular exercise can impose differential processes that lead to the formation of either healthy or unhealthy adipose tissue and discuss key knowledge gaps that warrant future research.

Comparison of two cell-free therapeutics derived from adipose tissue: small extracellular vesicles versus conditioned medium

BackgroundCell-free therapy has been inspired as a promising approach to overcome the limitations of traditional stem cell therapy. However, the therapeutic effect between extracellular vesicles and conditioned medium with the same source had not been compared. Our previous studies have shown that both the conditioned medium of adipose tissue (adipose tissue extract, ATE) and its further purification product small extracellular vesicles (sEV-AT) contributed to adipose tissue regeneration. In this study, we aimed to compare the ATE and sEV-AT in composition, inductivity on cells and de novo adipose regenerative potential.MethodsThe characteristics of sEV-AT and ATE were compared through protein and particle yield, particle size distribution and composition. The inductivity of sEV-AT and ATE on cells were compared through co-culture of sEV-AT or ATE with ASC, HUVEC and RAW264.7 in vitro. The capacity of promoting de novo adipogenesis was compared by implanting the silicone tube containing sEV-AT or ATE subcutaneously in vivo.ResultsMore particles and concentrated particle size distribution were detected in sEV-AT. In turn, more soluble factors and multiple peaks in particle size distribution were detected in ATE. In 1662 common proteins of sEV-AT and ATE, there were 984 (59.2%) proteins enriched twice more in sEV-AT than in ATE. With the prerequisite of equivalent protein concentration, sEV-AT outperformed ATE in promoting proliferation, migration and regeneration potential of cells those contributing adipose tissue regeneration in vitro. Furthermore, sEV-AT expedited the de novo adipose tissue regeneration and angiogenesis at the early stage than ATE in vivo, but sEV-AT and ATE group formed similar neoadipose tissue and new vessels at week 12.ConclusionsOur results provided a direct comparison between EV and conditioned medium as cell-free therapeutic strategy. Both sEV and ATE had specific biological signature to facilitate tissue repair. Considering the convenience of extraction and acceptable effect, ATE represented a feasible product of cell-free therapy, providing another option for different situations in clinical application. Furthermore, the complex contents of both sEV-AT and ATE should be studied comprehensively to avoid possible negative effects and to ensure sufficient safety for clinical applications.

Effects of adipose-derived stromal cells and endothelial progenitor cells on adipose transplant survival and angiogenesis.

BackgroundA paracrine mechanism is thought to mediate the proangiogenic capacity of adipose-derived stromal/stem cells (ASCs). However, the precise mechanism by which ASCs promote the formation of blood vessels by endothelial progenitor cells (EPCs) is unclear.MethodsThe EPCs-ASCs cocultures prepared in different ratios were subjected to tube formations assay to verify whether ASCs could directly participate in the tube genesis. The supernatant from cultured ASCs was used to stimulate EPCs to evaluate the effects on the angiogenic property of EPCs, as well as capacity for migration and invasion. A coculture model with transwell chamber were used to explore the regulation of angiogenesis markers expression in EPCs by ASCs. We then mixed ASCs with EPCs and transplanted them with adipose tissue into nude mice to evaluate the effects on angiogenesis in adipose tissue grafts.ResultsIn the EPCs-ASCs cocultures, the tube formation was significantly decreased as the relative abundance of ASCs increased, while the ASCs was found to migrate and integrated into the agglomerates formed by EPCs. The supernatant from ASCs cultures promoted the migration and invasion of EPCs and the ability to form capillary-like structures. The expression of multiple angiogenesis markers in EPCs were significantly increased when cocultured with ASCs. In vivo, ASCs combined with EPC promoted vascularization in the fat transplant. Immunofluorescence straining of Edu and CD31 indicated that the Edu labeled EPC did not directly participate in the vascularization inside the fat tissue.ConclusionsADSC can participate in the tube formation of EPC although it cannot form canonical capillary structures. Meanwhile, Soluble factors secreted by ASCs promotes the angiogenic potential of EPCs. ASCs paracrine signaling appears to promote angiogenesis by increasing the migration and invasion of EPCs and simultaneously upregulating the expression of angiogenesis markers in EPCs. The results of in vivo experiments showed that ASCs combined with EPCs significantly promote the formation of blood vessels in the fat implant. Remarkably, EPCs may promote angiogenesis by paracrine regulation of endogenous endothelial cells (ECs) rather than direct participation in the formation of blood vessels.

Effects of 8 Weeks Resistance Training on the Expression of MicroRNAs Associated With Adipose Tissue Angiogenesis in Rats on a High-Fat Diet

Background and Aim: Recent research has shown that microRNAs (miRNAs) can be regarded as new biomarkers for metabolic and angiogenesis-related diseases. This study aimed to investigate the effect of 8 weeks of resistance training on the expression of miRNAs associated with adipose tissue angiogenesis in rats with a high-fat diet. Materials and Methods: Forty male Wistar rats were randomly divided into four groups (each with 10 rats): normal diet, normal diet+resistance training, high-fat diet, and high-fat diet+resistance training. The resistance training groups performed 5 sessions of resistance training protocol each week for 8 weeks. After one week of familiarity with ladders, in the 2nd week, weights of 30% of body weight were attached to the rats’ tails, which gradually reached about 180% of their body weight by the end of 8 weeks. To evaluate the effect of resistance training and a high-fat diet on miR-221, miR-222, miR-329, and vascular endothelial growth factor (VEGF) variables, sampling of mesenteric adipose tissue was performed immediately after killing the animals. Results: The levels of miR-221, miR-222, and VEGF in the resistance training group+normal diet and resistance training group+high-fat diet increased significantly compared to the control groups (P=0.001, and P=0.001, respectively). However, no significant difference was observed in any groups regarding miR-329 (P=0.103). Conclusion: The results showed that resistance training increased microRNAs levels associated with adipose tissue angiogenesis in rats on a high-fat and normal diet.

Depot- and Diabetes-Specific Differences in Norepinephrine-Mediated Adipose Tissue Angiogenesis, Vascular Tone, Collagen Deposition and Morphology in Obesity

Depot- and Diabetes-Specific Differences in Norepinephrine-Mediated Adipose Tissue Angiogenesis, Vascular Tone, Collagen Deposition and Morphology in Obesity