angiogenic potential
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PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0261498
Author(s):  
Fengshan Gan ◽  
Liu Liu ◽  
Qingzhu Zhou ◽  
Wenli Huang ◽  
Xinwei Huang ◽  
...  

Background A 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. Methods The 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. Results In 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. Conclusions ADSC 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.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Liping Su ◽  
Xiaocen Kong ◽  
Szejie Loo ◽  
Yu Gao ◽  
Bingli Liu ◽  
...  

Abstract Background Prior studies show that signature phenotypes of diabetic human induced pluripotent stem cells derived endothelial cells (dia-hiPSC-ECs) are disrupted glycine homeostasis, increased senescence, impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. In the current study, we aimed to assess the role of thymosin β-4 (Tb-4) on endothelial function using dia-hiPSC-ECs as disease model of endothelial dysfunction. Methods and results Using dia-hiPSC-ECs as models of endothelial dysfunction, we determined the effect of Tb-4 on cell proliferation, senescence, cyto-protection, protein expression of intercellular adhesion molecule-1 (ICAM-1), secretion of endothelin-1 and MMP-1, mitochondrial membrane potential, and cyto-protection in vitro and angiogenic potential for treatment of ischemic limb disease in a mouse model of type 2 diabetes mellitus (T2DM) in vivo. We found that 600 ng/mL Tb4 significantly up-regulated AKT activity and Bcl-XL protein expression, enhanced dia-hiPSC-EC viability and proliferation, limited senescence, reduced endothelin-1 and MMP-1 secretion, and improved reparative potency of dia-hiPSC-ECs for treatment of ischemic limb disease in mice with T2DM. However, Tb4 had no effect on improving mitochondrial membrane potential and glycine homeostasis and reducing intercellular adhesion molecule-1 protein expression in dia-hiPSC-ECs. Conclusions Tb-4 improves endothelial dysfunction through enhancing hiPSC-EC viability, reducing senescence and endothelin-1 production, and improves angiogenic potency in diabetes.


2022 ◽  
Author(s):  
Xiaohui Wang ◽  
Chao Jiang ◽  
Yongyuan Zhang ◽  
Zhe Chen ◽  
Hong Fan ◽  
...  

Abstract ObjectiveThe aim of this study was to investigate the pro-angiogenic potential of olfactory ensheathing cells (OECs) activated by curcumin (CCM) and lipopolysaccharide (LPS) and the possible underlying mechanisms. MethodsVascular endothelial cells or tissues were cultured and treated with conditioned medium (CM) extracted from the activated through the addition of LPS and CCM or unactivated OECs. Concomitantly, the pro-angiogenic potential of OECs was assessed in vitro by aortic ring sprouting assay, endothelial wound healing assay, CCK-8 assay and tube formation assay. Subsequently, the OECs were co-cultured with endothelial cells to evaluate their promoting effect on the proliferation and migration of endothelial cells following undergoing a mechanical scratch. Moreover, the spinal cord injury (SCI) model in rats was established, and the number of endothelial cells and vascular structure in the injured area after SCI was observed with OECs transplantation. Finally, the underlying mechanism was investigated by western blot analysis of phosphorylated kinase expression with or without the MK-2206 (Akt-inhibitor). ResultThe present results showed that the activated OECs can effectively promote the proliferation, migration and vessel-like structure formation of vascular endothelial cells. Strikingly, several pro-angiogenic growth factors such as VEGF-A and PDGF-AA, which facilitate vessel formation, were found to be significantly elevated in CM. In addition, the PI3K/Akt signaling pathway involved in pro-angiogenic event caused by activated OEC CM, displaying higher phosphorylation levels in cells. On contrary, the delivery of MK2206 can effectively abrogate all the positive effects. ConclusionsOECs activated by LPS and CCM, have a strong pro-angiogenesis effect, and can effectively promote angiogenesis and improve the injury microenvironment when transplanted in injured spinal cord. This potentiated ability of OECs to pro-angiogenesis is likely mediated through the PI3K/Akt pathway.


Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 51
Author(s):  
Giovanni Giurdanella ◽  
Anna Longo ◽  
Alfio Distefano ◽  
Melania Olivieri ◽  
Martina Cristaldi ◽  
...  

Hyperglycemia-induced impairment of the blood-retinal barrier represents the main pathological event in diabetic retinopathy that is elicited by a reduced cellular response to an accumulation of reactive oxygen species (ROS) and increased inflammation. The purpose of the study was to evaluate whether the selective β1-adrenoreceptor (β1-AR) antagonist metoprolol could modulate the inflammatory response to hyperglycemic conditions. For this purpose, human retinal endothelial cells (HREC) were treated with normal (5 mM) or high glucose (25 mM, HG) in the presence of metoprolol (10 μM), epinephrine (1 μM), or both compounds. Metoprolol prevented both the HG-induced reduction of cell viability (MTT assays) and the modulation of the angiogenic potential of HREC (tube formation assays) reducing the TNF-α, IL-1β, and VEGF mRNA levels (qRT-PCR). Moreover, metoprolol prevented the increase in phospho-ERK1/2, phospho-cPLA2, COX2, and protein levels (Western blot) as well as counteracting the translocation of ERK1/2 and cPLA2 (high-content screening). Metoprolol reduced ROS accumulation in HG-stimulated HREC by activating the anti-oxidative cellular response mediated by the Keap1/Nrf2/HO-1 pathway. In conclusion, metoprolol exerted a dual effect on HG-stimulated HREC, decreasing the activation of the pro-inflammatory ERK1/2/cPLA2/COX2 axis, and counteracting ROS accumulation by activating the Keap1/Nrf2/HO-1 pathway.


Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 13
Author(s):  
Ekaterina A. Sokolenko ◽  
Utta Berchner-Pfannschmidt ◽  
Saskia C. Ting ◽  
Kurt W. Schmid ◽  
Nikolaos E. Bechrakis ◽  
...  

The treatment of uveal melanoma and its metastases has not evolved sufficiently over the last decades in comparison to other tumour entities, posing a great challenge in the field of ocular oncology. Despite improvements in the conventional treatment regime and new discoveries about the genetic and molecular background of the primary tumour, effective treatment strategies to either prevent tumours or treat patients with advanced or metastatic disease are still lacking. New therapeutic options are necessary in order to achieve satisfactory local tumour control, reduce the risk of metastasis development, and preserve the eyeball and possibly the visual function of the eye. The development of in vivo model systems remains crucial for the identification and investigation of potential novel treatment modalities. The aim of this study was the optimisation of the chorioallantoic membrane (CAM) model for uveal melanoma research. We analysed the established CAM assay and its modification after the implantation of three-dimensional spheroids. The chorioallantoic membrane of a chick embryo was used to implant uveal melanoma-cell-line-derived spheroids in order to study their growth rate, angiogenic potential, and metastatic capability. Using the UM 92.1, UPMD2, UPMM3, and Mel270 cell lines, we were able to improve the viability of the embryos from 20% to >80% and to achieve up to a fourfold volume increase of the transplanted spheroid masses. The results point to the value of an optimised chicken embryo assay as an in vivo model for testing novel therapies for uveal melanoma by simplifying the research conditions and by contributing to a considerable reduction in animal experiments.


2021 ◽  
Vol 12 ◽  
Author(s):  
Devy Zisman ◽  
Mirna Safieh ◽  
Elina Simanovich ◽  
Joy Feld ◽  
Amalia Kinarty ◽  
...  

BackgroundAngiogenesis is a major contributor to the development of inflammation during Rheumatoid arthritis (RA), as the vascularization of the pannus provides nutrients and oxygen for the infiltrating immune cells and proliferating synoviocytes. Tocilizumab (TCZ) is an anti-IL-6 receptor antibody that is used in the treatment of RA patients, and has been shown to exert anti-inflammatory effects. However, its effects on angiogenesis are not fully elucidated, and the molecular mechanisms regulating this effect are unknown.MethodsWe evaluated the concentrations of several pro- and anti-angiogenic factors and the expression levels of several microRNA molecules that are associated with RA and angiogenesis in serum samples obtained from 40 RA patients, before and 4 months after the initiation of TCZ treatment. Additionally, we used an in vitro co-culture system of fibroblasts (the HT1080 cell line) and monocytes (the U937 cell line) to explore the mechanisms of TCZ action.ResultsSerum samples from RA patients treated with TCZ exhibited reduced circulating levels of EMMPRIN/CD147, enhanced expression of circulating miR-146a-5p and miR-150-5p, and reduced the angiogenic potential as was manifested by the lower number of tube-like structures that were formed by EaHy926 endothelial cell line. In vitro, the accumulation in the supernatants of the pro-angiogenic factors EMMPRIN, VEGF and MMP-9 was increased by co-culturing the HT1080 fibroblasts and the U937 monocytes, while the accumulation of the anti-angiogenic factor thrombospondin-1 (Tsp-1) and the expression levels of miR-146a-5p were reduced. Transfection of HT1080 cells with the miR-146a-5p mimic, decreased the accumulation of EMMPRIN, VEGF and MMP-9. When we neutralized EMMPRIN with a blocking antibody, the supernatants derived from these co-cultures displayed reduced migration, proliferation and tube formation in the functional assays.ConclusionsOur findings implicate miR-146a-5p in the regulation of EMMPRIN and propose that TCZ affects angiogenesis through its effects on EMMPRIN and miR-146a-5p.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3493
Author(s):  
Yasser Basmaeil ◽  
Eman Bahattab ◽  
Abdullah Al Subayyil ◽  
Haya Kulayb ◽  
Maha Alrodayyan ◽  
...  

Mesenchymal stem cells (MSCs) have been shown to suppress tumor growth, inhibit angiogenesis, regulate cellular signaling, and induce apoptosis in cancer cells. We have earlier reported that placenta-derived decidua parietalis mesenchymal stem/stromal cells (DPMSCs) not only retained their functional characteristics in the cancer microenvironment but also exhibited increased expression of anti-apoptotic genes, demonstrating their anti-tumor properties in the tumor setting. In this study, we have further evaluated the effects of DPMSCs on the functional outcome of human breast cancer cell line MDA231. MDA231 cells were exposed to DPMSCs, and their biological functions, including adhesion, proliferation, migration, and invasion, were evaluated. In addition, genomic and proteomic modifications of the MDA231 cell line, in response to the DPMSCs, were also evaluated. MDA231 cells exhibited a significant reduction in proliferation, migration, and invasion potential after their treatment with DPMSCs. Furthermore, DPMSC treatment diminished the angiogenic potential of MDA231 cells. DPMSC treatment modulated the expression of various pro-apoptotic as well as oncogenes in MDA231 cells. The properties of DPMSCs to inhibit the invasive characteristics of MDA231 cells demonstrate that they may be a useful candidate in a stem-cell-based therapy against cancer.


2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Haobo Zhong ◽  
Jin Qian ◽  
Zhihong Xiao ◽  
Yan Chen ◽  
Xiangchun He ◽  
...  

Diabetic foot ulcers (DFUs) are caused by impairments in peripheral blood vessel angiogenesis and represent a great clinical challenge. Although various innovative techniques and drugs have been developed for treating DFUs, therapeutic outcomes remain unsatisfactory. Using the GEO database, we obtained transcriptomic microarray data for DFUs and control wounds and detected a significant downregulation of epidermal growth factor receptor (EGFR) in DFUs. We cultured human umbilical vein endothelial cells (HUVECs) and noted downregulated EGFR expression following high-glucose exposure in vitro. Further, we observed decreased HUVEC proliferation and migration and increased apoptosis after shRNA-mediated EGFR silencing in these cells. In mice, EGFR inhibition via focal EGFR-shRNA injection delayed wound healing. Target prediction analysis followed by dual-luciferase reporter assays indicated that microRNA-133b (miR-133b) is a putative upstream regulator of EGFR expression. Increased miR-133b expression was observed in both glucose-treated HUVECs and wounds from diabetes patients, but no such change was observed in controls. miR-133b suppression enhanced the proliferation and angiogenic potential of cultured HUVECs and also accelerated wound healing. Although angiogenesis is not the sole mechanism affected in DFU, these findings suggest that the miR-133b-induced downregulation of EGFR may contribute to delayed wound healing in diabetes. Hence, miR-133b inhibition may be a useful strategy for treating diabetic wounds.


2021 ◽  
Vol 10 (23) ◽  
pp. 5516
Author(s):  
Óscar Osorio-Conles ◽  
Josep Vidal ◽  
Ana de Hollanda

Bariatric surgery (BS) procedures are actually the most effective intervention to help subjects with severe obesity achieve significant and sustained weight loss. White adipose tissue (WAT) is increasingly recognized as the largest endocrine organ. Unhealthy WAT expansion through adipocyte hypertrophy has pleiotropic effects on adipocyte function and promotes obesity-associated metabolic complications. WAT dysfunction in obesity encompasses an altered adipokine secretome, unresolved inflammation, dysregulated autophagy, inappropriate extracellular matrix remodeling and insufficient angiogenic potential. In the last 10 years, accumulating evidence suggests that BS can improve the WAT function beyond reducing the fat depot sizes. The causal relationships between improved WAT function and the health benefits of BS merits further investigation. This review summarizes the current knowledge on the short-, medium- and long-term outcomes of BS on the WAT composition and function.


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