angiogenesis

摘要： We previously combined reduced graphene oxide(rGO)with gelatin-methacryloyl(GelMA)and polycaprolactone(PCL)to create an rGO-GelMA-PCL nerve conduit and found that the conductivity and biocompatibility were improved.However,the rGO-GelMA-PCL nerve conduits differed greatly from autologous nerve transplants in their ability to promote the regeneration of injured peripheral nerves and axonal sprouting.Extracellular vesicles derived from bone marrow mesenchymal stem cells(BMSCs)can be loaded into rGO-GelMA-PCL nerve conduits for repair of rat sciatic nerve injury because they can promote angiogenesis at the injured site.In this study,12 weeks after surgery,sciatic nerve function was measured by electrophysiology and sciatic nerve function index,and myelin sheath and axon regeneration were observed by electron microscopy,immunohistochemistry,and immunofluorescence.The regeneration of microvessel was observed by immunofluorescence.Our results showed that rGO-GelMA-PCL nerve conduits loaded with BMSC-derived extracellular vesicles were superior to rGO-GelMA-PCL conduits alone in their ability to increase the number of newly formed vessels and axonal sprouts at the injury site as well as the recovery of neurological function.These findings indicate that rGO-GelMA-PCL nerve conduits loaded with BMSC-derived extracellular vesicles can promote peripheral nerve regeneration and neurological function recovery,and provide a new direction for the curation of peripheral nerve defect in the clinic.

摘要： Inhibiting retinal neovascularization is the optimal strategy for the treatment of retina-related diseases, but there is currently no effective treatment for retinal neovascularization. P-element-induced wimpy testis(PIWI)-interacting RNA(piRNA) is a type of small non-coding RNA implicated in a variety of diseases. In this study, we found that the expression of piR-1245 and the interacting protein PIWIL2 were remarkably increased in human retinal endothelial cells cultured in a hypoxic environment, and cell apoptosis, migration, tube formation and proliferation were remarkably enhanced in these cells. Knocking down piR-1245 inhibited the above phenomena. After intervention by a p-JAK2 activator, piR-1245 decreased the expression of hypoxia inducible factor-1α and vascular endothelial growth factor through the JAK2/STAT3 pathway. For in vivo analysis, 7-day-old newborn mice were raised in 75 ± 2% hyperoxia for 5 days and then piR-1245 in the retina was knocked down. In these mice, the number of newly formed vessels in the retina was decreased, the expressions of inflammationrelated proteins were reduced, the number of apoptotic cells in the retina was decreased, the JAK2/STAT3 pathway was inhibited, and the expressions of hypoxia inducible factor-1α and vascular endothelial growth factor were decreased. Injection of the JAK2 inhibitor JAK2/TYK2-IN-1 into the vitreous cavity inhibited retinal neovascularization in mice and reduced expression of hypoxia inducible factor-1α and vascular endothelial growth factor. These findings suggest that piR-1245 activates the JAK2/STAT3 pathway, regulates the expression of hypoxia inducible factor-1α and vascular endothelial growth factor, and promotes retinal neovascularization. Therefore, piR-1245 may be a new therapeutic target for retinal neovascularization.

摘要： Neovascularization and angiogenesis in the brain are important physiological processes for normal brain development and repair/regeneration following insults. Integrins are cell surface adhesion receptors mediating important function of cells such as survival, growth and development during tissue organization, differentiation and organogenesis. In this study, we used an integrin-binding array platform to identify the important types of integrins and their binding peptides that facilitate adhesion, growth, development, and vascular-like network formation of rat primary brain microvascular endothelial cells. Brain microvascular endothelial cells were isolated from rat brain on post-natal day 7. Cells were cultured in a custom-designed integrin array system containing short synthetic peptides binding to 16 types of integrins commonly expressed on cells in vertebrates. After 7 days of culture, the brain microvascular endothelial cells were processed for immunostaining with markers for endothelial cells including von Willibrand factor and platelet endothelial cell adhesion molecule. 5-Bromo-2′-dexoyuridine was added to the culture at 48 hours prior to fixation to assess cell proliferation. Among 16 integrins tested, we found that α5β1, αvβ5 and αvβ8 greatly promoted proliferation of endothelial cells in culture. To investigate the effect of integrin-binding peptides in promoting neovascularization and angiogenesis, the binding peptides to the above three types of integrins were immobilized to our custom-designed hydrogel in three-dimensional(3 D) culture of brain microvascular endothelial cells with the addition of vascular endothelial growth factor. Following a 7-day 3 D culture, the culture was fixed and processed for double labeling of phalloidin with von Willibrand factor or platelet endothelial cell adhesion molecule and assessed under confocal microscopy. In the 3 D culture in hydrogels conjugated with the integrin-binding peptide, brain microvascular endothelial cells formed interconnected vascular-like network with clearly discernable lumens, which is reminiscent of brain microvascular network in vivo. With the novel integrin-binding array system, we identified the specific types of integrins on brain microvascular endothelial cells that mediate cell adhesion and growth followed by functionalizing a 3 D hydrogel culture system using the binding peptides that specifically bind to the identified integrins, leading to robust growth and lumenized microvascular-like network formation of brain microvascular endothelial cells in 3 D culture. This technology can be used for in vitro and in vivo vascularization of transplants or brain lesions to promote brain tissue regeneration following neurological insults.

摘要： Cervical spondylotic myelopathy is the main cause of non-traumatic spinal cord injury,with chronic static and/or dynamic compressive spinal cord injury as the unique pathogenesis.In the progression of this condition,the microvascular network is compressed and destroyed,resulting in ischemia and hypoxia.The main pathological changes are inflammation,damage to the blood spinal cord barriers,and cell apoptosis at the site of compression.Studies have confirmed that vascular regeneration and remodeling contribute to neural repair by promoting blood flow and the reconstruction of effective circulation to meet the nutrient and oxygen requirements for nerve repair.Surgical decompression is the most effective clinical treatment for this condition;however,in some patients,residual neurological dysfunction remains after decompression.Facilitating revascularization during compression and after decompression is therefore complementary to surgical treatment.In this review,we summarize the progress in research on chronic compressive spinal cord injury,covering both physiological and pathological changes after compression and decompression,and the regulatory mechanisms of vascular injury and repair.

摘要： Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of angiogenesis during the regeneration process,we hypothesized that metformin activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway in endothelial cells,thereby promoting microvascular regeneration in aged mice after spinal cord injury.In this study,we established young and aged mouse models of contusive spinal cord injury using a modified Allen method.We found that aging hindered the recovery of neurological function and the formation of blood vessels in the spinal cord.Treatment with metformin promoted spinal cord microvascular endothelial cell migration and blood vessel formation in vitro.Furthermore,intraperitoneal injection of metformin in an in vivo model promoted endothelial cell proliferation and increased the density of new blood vessels in the spinal cord,thereby improving neurological function.The role of metformin was reversed by compound C,an adenosine monophosphate-activated protein kinase inhibitor,both in vivo and in vitro,suggesting that the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway likely regulates metformin-mediated angiogenesis after spinal cord injury.These findings suggest that metformin promotes vascular regeneration in the injured spinal cord by activating the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway,thereby improving the neurological function of aged mice after spinal cord injury.

摘要： The introduction of neurotrophic factors into injured peripheral nerve sites is beneficial to peripheral nerve regeneration.However,neurotrophic facto rs are rapidly degraded in vivo and obstruct axonal regeneration when used at a supraphysiological dose,which limits their clinical benefits.Bioactive mimetic peptides have been developed to be used in place of neurotrophic factors because they have a similar mode of action to the original growth fa ctors and can activate the equivalent receptors but have simplified sequences and structures.In this study,we created polydopamine-modified chitin conduits loaded with brain-derived neurotrophic factor mimetic peptides and vascular endothelial growth fa ctor mimetic peptides(Chi/PDA-Ps).We found that the Chi/PDA-Ps conduits were less cytotoxic in vitro than chitin conduits alone and provided sustained release of functional peptides.In this study,we evaluated the biocompatibility of the Chi/P DA-Ps conduits.Brain-derived neurotrophic factor mimetic peptide and vascular endothelial growth fa ctor mimetic peptide synergistically promoted prolife ration of Schwann cells and secretion of neurotrophic factors by Schwann cells and attachment and migration of endothelial cells in vitro.The Chi/P DA-Ps conduits were used to bridge a 2 mm gap between the nerve stumps in rat models of sciatic nerve injury.We found that the application of Chi/PDA-Ps conduits could improve the motor function of rats and reduce gastrocnemius atrophy.The electrophysiological results and the microstructure of regenerative nerves showed that the nerve conduction function and re myelination was further resto red.These findings suggest that the Chi/PDA-Ps conduits have great potential in peripheral nerve injury repair.

摘要： Ovarian malignancies are the most complicated type among all gynecological cancers.Their etiology is yet unknown;however,they are a heterogeneous,rapidly growing,and very fatal group of cancers.Chronic inflammation and angiogenesis appear to have major contributions in the development and progression of ovarian malignancies.Angiogenesis and inflammation are involved in the pathogenesis of ovarian cancer.Vitamin D3(VitD3)has shown to have anti-inflammatory and anti-angiogenic properties in different types of cancers.The anti-inflammatory and anti-angiogenesis effects of VitD3 on ovarian cancer are investigated in this review.

摘要： BACKGROUND Sustained injury,through radiotherapy,burns or surgical trauma,can result in fibrosis,displaying an excessive deposition of extracellular matrix(ECM),persisting inflammatory reaction,and reduced vascularization.The increasing recognition of fibrosis as a cause for disease and mortality,and increasing use of radiotherapy causing fibrosis,stresses the importance of a decent anti-fibrotic treatment.AIM To obtain an in-depth understanding of the complex mechanisms underlying fibrosis,and more specifically,the potential mechanisms-of-action of adiposederived stomal cells(ADSCs)in realizing their anti-fibrotic effect.METHODS A systematic review of the literature using PubMed,Embase and Web of Science was performed by two independent reviewers.RESULTS The injection of fat grafts into fibrotic tissue,releases ADSC into the environment.ADSCs’capacity to directly differentiate into key cell types(e.g.,ECs,fibroblasts),as well as to secrete multiple paracrine factors(e.g.,hepatocyte growth factor,basis fibroblast growth factor,IL-10),allows them to alter different mechanisms underlying fibrosis in a combined approach.ADSCs favor ECM degradation by impacting the fibroblast-to-myofibroblast differentiation,favoring matrix metalloproteinases over tissue inhibitors of metalloproteinases,positively influencing collagen organization,and inhibiting the pro-fibrotic effects of transforming growth factor-β1.Furthermore,they impact elements of both the innate and adaptive immune response system,and stimulate angiogenesis on the site of injury(through secretion of pro-angiogenic cytokines like stromal cell-derived factor-1 and vascular endothelial growth factor).CONCLUSION This review shows that understanding the complex interactions of ECM accumulation,immune response and vascularization,is vital to fibrosis treatments’effectiveness like fat grafting.It details how ADSCs intelligently steer this complex system in an anti-fibrotic or pro-angiogenic direction,without falling into extreme dilation or stimulation of a single aspect.Detailing this combined approach,has brought fat grafting one step closer to unlocking its full potential as a non-anecdotal treatment for fibrosis.

摘要： Brain-derived neurotrophic factor (BDNF) has been considered a new angiogenesis mediator. ProBDNF, the precursor of BDNF, plays opposite neuronal functions to BDNF, but the role of proBDNF on angiogenesis remains unknown. We found human umbilical vein endothelial cells (HUVEC) expressing BDNF, proBDNF, p75NTR, Sortilin and TrkB. ProBDNF significantly decreased HUVEC viability in MTT assay, and this inhibition was neutralized by anti-proBDNF. Endothelial cell tube formation assay showed that proBDNF significantly inhibits HUVEC angiogenesis in vitro. Matrigel plug assay disclosed that proBDNF also impeded angiogenesis in vivo, while anti-proBDNF greatly facilitated angiogenesis. Immunostaining of CD31 and α-SMA in Matrigel plugs confirmed the inhibitive effect of proBDNF on angiogenesis. In conclusion, proBDNF can act as an angiogenesis inhibitor. It added more evidence to the “Yin-Yang” theory by showing mBDNF is a mediator of angiogenesis as “Yang” and proBDNF works as an angiogenesis inhibitor as “Yin”.

摘要： Extracellular vesicles are composed of fragments of exfoliated plasma membrane,organelles or nuclei and are released after cell activation,apoptosis or destruction.Platelet-derived extracellular vesicles are the most abundant type of extracellular vesicle in the blood of patients with traumatic brain injury.Accumulated laboratory and clinical evidence shows that platelet-derived extracellular vesicles play an important role in coagulopathy and inflammation after traumatic brain injury.This review discusses the recent progress of research on platelet-derived extracellular vesicles in coagulopathy and inflammation and the potential of platelet-derived extracellular vesicles as therapeutic targets for traumatic brain injury.