Role of melatonin in the angiogenesis potential; highlights on the cardiovascular disease

Rahbarghazi, Afshin; Siahkouhian, Marefat; Rahbarghazi‬, Reza; Ahmadi, Mahdi; Bolboli, Lotfali; Keyhanmanesh, ‬Rana; Mahdipour, Mahdi; Rajabi, Hadi

doi:10.1186/s12950-021-00269-5

Cited by 20 publications

(9 citation statements)

References 86 publications

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“…It has been indicated that the exposure of hypoxic cells to melatonin can reduce the production of angiogenesis factors [ 39 ]. Melatonin can diminish the expression of HIF-1α via the neutralization of reactive oxygen species and regulation of Sphingosine kinase 1 activity and TGF-β signaling pathway [ 40 , 39 , 41 ]. The reduction of reactive oxygen species and down-regulation of VEGF were documented in hypoxic ECs treated with melatonin [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Melatonin blunted the angiogenic activity in 3D colon cancer tumoroids by the reduction of endocan

Narmi,

Shoja,

Haiaty

et al. 2023

Cancer Cell Int

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Background Complexity and heterogeneity of the tumor niche are closely associated with the failure of therapeutic protocols. Unfortunately, most data have been obtained from conventional 2D culture systems which are not completely comparable to in vivo microenvironments. Reconstructed 3D cultures composed of multiple cells are valid cell-based tumor models to recapitulate in vivo-like interaction between the cancer cells and stromal cells and the oncostatic properties of therapeutics. Here, we aimed to assess the tumoricidal properties of melatonin on close-to-real colon cancer tumoroids in in vitro conditions. Methods Using the hanging drop method, colon cancer tumoroids composed of three cell lines, including adenocarcinoma HT-29 cells, fibroblasts (HFFF2), and endothelial cells (HUVECs) at a ratio of 2: 1: 1, respectively were developed using 2.5% methylcellulose. Tumoroids were exposed to different concentrations of melatonin, from 0.005 to 0.8 mM and 4 to 10 mM, for 48 h. The survival rate was measured by MTT and LDH leakage assays. Protein levels of endocan and VEGF were assessed using western blotting. Using histological examination (H & E) staining, the integrity of cells within the tumoroid parenchyma was monitored. Results Despite the reduction of viability rate in lower doses, the structure of tumoroids remained unchanged. In contrast, treatment of tumoroids with higher doses of melatonin, 4 and 10 mM, led to disaggregation of cells and reduction of tumoroid diameter compared to the non-treated control tumoroids (p < 0.05). By increasing melatonin concentration from 4 to 10 mM, the number of necrotic cells increased. Data showed the significant suppression of endocan in melatonin-treated tumoroids related to the non-treated controls (p < 0.05). According to our data, melatonin in higher doses did not alter protein levels of VEGF (p > 0.05). Conclusions Melatonin can exert its tumoricidal properties on colon cancer tumoroids via the reduction of tumor cell viability and inhibition of the specific pro-angiogenesis factor.

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Section: Discussionmentioning

confidence: 99%

Melatonin blunted the angiogenic activity in 3D colon cancer tumoroids by the reduction of endocan

Narmi,

Shoja,

Haiaty

et al. 2023

Cancer Cell Int

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“…The addition of Mel was done with the respect to the fact that this hormone can blunt the detrimental effects of reactive free radicals in the early days after transplantation before the formation of de novo vessels [ 33 , 34 ]. Besides, this hormone can increase the local content of pro-angiogenesis factors from ECs and immune cell origin [ 35 ]. According to our data, Mel- and ECs-free Alg + Fib hydrogels lack eligibility to induce angiogenesis as compared to the FT group.…”

Section: Discussionmentioning

confidence: 99%

Melatonin and endothelial cell-loaded alginate-fibrin hydrogel promoted angiogenesis in rat cryopreserved/thawed ovaries transplanted to the heterotopic sites

et al. 2023

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Background Ischemic niche can promote follicular atresia following the transplantation of cryopreserved/thawed ovaries to the heterotopic sites. Thus, the promotion of blood supply is an effective strategy to inhibit/reduce the ischemic damage to ovarian follicles. Here, the angiogenic potential of alginate (Alg) + fibrin (Fib) hydrogel enriched with melatonin (Mel) and CD144+ endothelial cells (ECs) was assessed on encapsulated cryopreserved/thawed ovaries following transplantation to heterotopic sites in rats. Methods Alg + Fib hydrogel was fabricated by combining 2% (w/v) sodium Alg, 1% (w/v) Fib, and 5 IU thrombin at a ratio of 4: 2: 1, respectively. The mixture was solidified using 1% CaCl2. Using FTIR, SEM, swelling rate, and biodegradation assay, the physicochemical properties of Alg + Fib hydrogel were evaluated. The EC viability was examined using an MTT assay. Thirty-six adult female rats (aged between 6 and 8 weeks) with a normal estrus cycle were ovariectomized and enrolled in this study. Cryopreserved/thawed ovaries were encapsulated in Alg + Fib hydrogel containing 100 µM Mel + CD144+ ECs (2 × 104 cells/ml) and transplanted into the subcutaneous region. Ovaries were removed after 14 days and the expression of Ang-1, and Ang-2 was monitored using real-time PCR assay. The number of vWF+ and α-SMA+ vessels was assessed using IHC staining. Using Masson’s trichrome staining, fibrotic changes were evaluated. Results FTIR data indicated successful interaction of Alg with Fib in the presence of ionic cross-linker (1% CaCl2). Data confirmed higher biodegradation and swelling rates in Alg + Fib hydrogel compared to the Alg group (p < 0.05). Increased viability was achieved in encapsulated CD144+ ECs compared to the control group (p < 0.05). IF analysis showed the biodistribution of Dil+ ECs within hydrogel two weeks after transplantation. The ratio of Ang-2/Ang-1 was statistically up-regulated in the rats that received Alg + Fib + Mel hydrogel compared to the control-matched groups (p < 0.05). Based on the data, the addition of Mel and CD144+ ECs to Alg + Fib hydrogel reduced fibrotic changes. Along with these changes, the number of vWF+ and α-SMA+ vessels was increased in the presence of Mel and CD144+ ECs. Conclusions Co-administration of Alg + Fib with Mel and CD144+ ECs induced angiogenesis toward encapsulated cryopreserved/thawed ovarian transplants, resulting in reduced fibrotic changes.

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“…Additionally, in the AP, Wnt Inhibitory Factor-1 knockout mice displayed an elevated level of the GLUT1 BBB marker [ 29 ], suggesting that locally expressed endogenous inhibitors of Wnt/β-catenin signaling suppress vEC’s β-catenin activities to prevent BBB formation in the fenestrated vascular beds of the brain. Melatonin, a hormone secreted by the PG, has been implied in the regulation of angiogenesis [ 205 ], especially inhibition of multiple tumor angiogenesis; however, its role in fenestrated capillary development or maintenance in the PG remains unclear.…”

Section: Development and Maintenance Of Endothelial Fenestrations And...mentioning

confidence: 99%

Historical and current perspectives on blood endothelial cell heterogeneity in the brain

Matsuoka

Buck

Vajrala

et al. 2022

Cell. Mol. Life Sci.

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Dynamic brain activity requires timely communications between the brain parenchyma and circulating blood. Brain–blood communication is facilitated by intricate networks of brain vasculature, which display striking heterogeneity in structure and function. This vascular cell heterogeneity in the brain is fundamental to mediating diverse brain functions and has long been recognized. However, the molecular basis of this biological phenomenon has only recently begun to be elucidated. Over the past century, various animal species and in vitro systems have contributed to the accumulation of our fundamental and phylogenetic knowledge about brain vasculature, collectively advancing this research field. Historically, dye tracer and microscopic observations have provided valuable insights into the anatomical and functional properties of vasculature across the brain, and these techniques remain an important approach. Additionally, recent advances in molecular genetics and omics technologies have revealed significant molecular heterogeneity within brain endothelial and perivascular cell types. The combination of these conventional and modern approaches has enabled us to identify phenotypic differences between healthy and abnormal conditions at the single-cell level. Accordingly, our understanding of brain vascular cell states during physiological, pathological, and aging processes has rapidly expanded. In this review, we summarize major historical advances and current knowledge on blood endothelial cell heterogeneity in the brain, and discuss important unsolved questions in the field.

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Role of melatonin in the angiogenesis potential; highlights on the cardiovascular disease

Cited by 20 publications

References 86 publications

Melatonin blunted the angiogenic activity in 3D colon cancer tumoroids by the reduction of endocan

Melatonin blunted the angiogenic activity in 3D colon cancer tumoroids by the reduction of endocan

Melatonin and endothelial cell-loaded alginate-fibrin hydrogel promoted angiogenesis in rat cryopreserved/thawed ovaries transplanted to the heterotopic sites

Historical and current perspectives on blood endothelial cell heterogeneity in the brain

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