Background:Ischemic retinopathies(IRs)are ocular disorders associated to microvascular degeneration leading to visual impairments and blindness.microRNA(miRNAs)are a family of non-coding RNAs that regulate a wide rang...Background:Ischemic retinopathies(IRs)are ocular disorders associated to microvascular degeneration leading to visual impairments and blindness.microRNA(miRNAs)are a family of non-coding RNAs that regulate a wide range of gene expression involved in various biological process such blood vessel development and pathological NV.However,the post-transcriptional modulation of miRs and especially,their specific functions in the eyes during IRs remain to be evaluated.We aim to evaluate the potential role of miR-96 on microvascular degeneration in a rat model of oxygen-induced retinopathy(OIR).Methods:In vivo:next generation sequencing(NSG)was used to perform a complete miRNAs profiling in the retina and choroid from OIR and normoxia(CTL)rats.To evaluate the effects of miR-96 on microvasculature,OIR animals were treated with a miR-96 mimic(1 mg/kg)or a control-miR by intravitreal injection before hyperoxia-exposure(80%O2).Immunostaining analysis of retinal flatmounts and cryosections was used to explore the microvascular effects of miR-96.In vitro:Human Retinal Microvascular Endothelial Cells(HRMVEC)were subjected or not to hyperoxia(80%O2)and transfected with 50 nM of miR-96 mimic or antagomir-96.Angiogenic assay was performed(tube formation and migration)and molecular analysis evaluated by qRT-PCR and western blot.Results:NSG and qRT-PCR analyses identified miR-96 as one of most highly expressed miRNAs in retina and choroid during development.However,miR-96 showed a strong downregulation in OIR rats,and also in HRMVEC subjected to hyperoxia.In HRMVEC,we found that miR-96 regulates positively the expression of the key pro-angiogenic factors VEGF,FGF-2 and ANG-2.To better explore the role of miR-96 on HRMVEC angiogenic activity,we performed a gain/loss of function study.Similarly,to hyperoxia exposure,we observed a robust angiogenic impairment(tube formation and migration)on HMRVEC transfected with an antagomiR-96.Interestingly,overexpression of miR-96 completely recued the basal phenotype of HRMVEC and protected against hyperoxia-induced endothelial dysfunction.In vivo,intravitreal injection of miR-96 mimic(1 mg/kg)in OIR rats significantly restored retinal vascular density and choroidal tightness/sprouting hability.This was accompanied by the restoration in the physiological levels of VEGF,FGF-2 and ANG-2.Conclusions:This is the first study showing that reduced expression of miR-96 in OIR conditions lead to a reduction of VEGF/FGF/ANG-2 signaling,and inneficient post-ischemic revascularization in retinal/choroidal tissues.Intravitreal supplementation of miR-96 using a miR mimic could constitute a novel therapeutic strategy to improve vascular repair in IRs.展开更多
Stem cells have shown great potential in vascular repair.Numerous evidence indicates that mechanical forces such as shear stress and cyclic strain can regulate the adhesion,proliferation,migration,and differentiation ...Stem cells have shown great potential in vascular repair.Numerous evidence indicates that mechanical forces such as shear stress and cyclic strain can regulate the adhesion,proliferation,migration,and differentiation of stem cells via serious signaling pathways.The enrichment and differentiation of stem cells play an important role in the angiogenesis and maintenance of vascular homeostasis.In normal tissues,blood flow directly affects the microenvironment of vascular endothelial cells(ECs);in pathological status,the abnormal interactions between blood flow and vessels contribute to the injury of vessels.Next,the altered mechanical forces are transduced into cells by mechanosensors to trigger the reformation of vessels.This process occurs when signaling pathways related to EC differentiation are initiated.Hence,a deep understanding of the responses of stem cells to mechanical stresses and the underlying mechanisms involved in this process is essential for clinical translation.In this the review,we provide an overview of the role of stem cells in vascular repair,outline the performance of stem cells under the mechanical stress stimulation,and describe the related signaling pathways.展开更多
Traumatic brain injury(TBI)disrupts normal brain function and is associated with high morbidity and fatality rates.TBI is characterized as mild,moderate or severe depending on its severity.The damage may be transient ...Traumatic brain injury(TBI)disrupts normal brain function and is associated with high morbidity and fatality rates.TBI is characterized as mild,moderate or severe depending on its severity.The damage may be transient and limited to the dura matter,with only subtle changes in cerebral parenchyma,or life-threatening with obvious focal contusions,hematomas and edema.Blood vessels are often injured in TBI.Even in mild TBI,dysfunctional cerebral vascular repair may result in prolonged symptoms and poor outcomes.Various distinct types of cells participate in vascular repair after TBI.A better understanding of the cellular response and function in vascular repair can facilitate the development of new therapeutic strategies.In this review,we analyzed the mechanism of cerebrovascular impairment and the repercussions following various forms of TBI.We then discussed the role of distinct cell types in the repair of meningeal and parenchyma vasculature following TBI,including endothelial cells,endothelial progenitor cells,pericytes,glial cells(astrocytes and microglia),neurons,myeloid cells(macrophages and monocytes)and meningeal lymphatic endothelial cells.Finally,possible treatment techniques targeting these unique cell types for vascular repair after TBI are discussed.展开更多
With adjustable amphiphilicity and anionic/cationic charge,biodegradability and biocompatibility,amino acid-based poly(ester amide)s(PEAs)have drawn attention in the research of tissue engineered vascular grafts.In th...With adjustable amphiphilicity and anionic/cationic charge,biodegradability and biocompatibility,amino acid-based poly(ester amide)s(PEAs)have drawn attention in the research of tissue engineered vascular grafts.In this work,L-phenylalanine-based PEAs with or without L-lysine were synthesized through polycondensation,and ultrafine fibrous grafts consisted of PEAs and poly(ε-caprolactone)(PCL)in given mass ratios were further prepared via blend electrospinning.Surface characterizations by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy confirmed the chemical structure,and the wettability indicated that the prepared PCL/PEAs electrospun membranes exhibited less hydrophobic than PCL.Tensile results showed that the PCL/PEAs membranes possessed suitable mechanical properties,which could meet the requirements of artificial blood vessels.Cell culture and hemolytic tests exhibited that the PCL/PEAs electrospun membranes are biocompatible.In general,the electrospun grafts of PCL/PEAs could be applied for vascular repair.展开更多
The exact molecular and cytological mechanism of how glucocorticoids induce vascular repair disorders in glucocorticoid-induced avascular necrosis of the femoral head is still unclear.We used bioinformatical tools for...The exact molecular and cytological mechanism of how glucocorticoids induce vascular repair disorders in glucocorticoid-induced avascular necrosis of the femoral head is still unclear.We used bioinformatical tools for data mining and detected the biological behavior of endothelial cells(ECs)under hypoxia conditions and high dose dexamethasone to reveal the mechanisms above.Six differential expression mi RNAs(DE-miRNAs)were filtered from Gene Expression Omnibus(GEO)database GSE60093 which contained ECs treated with high dose glucocorticoid and control samples.Enrichment and PPI network analyses of the DE-miRNAs target genes showed the most remarkable pathway was HIF-1 signaling pathway and high dose glucocorticoid as a negative regulator of cell differentiation,energy metabolism,migration and cytokines secretion.Glucocorticoids also reduced the activity of autocrine/paracrine via limiting ion channels and transmembrane transporter process.In cytological experiment,HUVECs were divided into four groups:hypoxia group(H),hypoxia+dexamethasone group(HD),dexamethasone group(D),the normal group(N).Cell activity detection and Live/Dead dyeing showed cell activity and the number of live cells in Group H was higher than the other three groups at 24 h after intervention,while cell activity,number and proportion of live cells in HD group were worst.Cytoskeleton staining showed HD group met cytoskeleton form disorders.The scratch assay showed cell migration ability of Group H was strongest while cell migration ability of the HD group was worst.MIF expression in HD group showed a trend of bimodal,the peak of VEGF-A secretion lagged behind the MIF’s.Expression of MIF and VEGF-A in the HD group were low.High dose dexamethasone suppressed the active response of ECs to hypoxia stimulation via directly inhibiting the expression of MIF and interdicting autocrine/paracrine mechanism.We infered that the treatment with high dose glucocorticoid would inhibit neo-angiogenesis under hypoxia followed by aggravating hypoxia/ischemia and osteonecrosis.展开更多
Bone is a highly vascularized tissue, although this aspect of bone is often overlooked. In this article, the importance of blood flow in bone repair and regeneration will be reviewed. First, the skeletal vascular anat...Bone is a highly vascularized tissue, although this aspect of bone is often overlooked. In this article, the importance of blood flow in bone repair and regeneration will be reviewed. First, the skeletal vascular anato- my, with an emphasis on long bones, the distinct mechanisms for vascularizing bone tissue, and methods for remodeling existing vasculature are discussed. Next, techniques for quantifying bone blood flow are briefly summarized. Finally, the body of experimental work that demonstrates the role of bone blood flow in fracture healing, distraction osteogenesis, osteoporosis, disuse osteopenia, and bone grafting is examined. These results illustrate that adequate bone blood flow is an important clinical consideration, particularly during bone regeneration and in at-risk patient groups.展开更多
Vascularization of acellular nerves has been shown to contribute to nerve bridging.In this study,we used a 10-mm sciatic nerve defect model in rats to determine whether cartilage oligomeric matrix protein enhances the...Vascularization of acellular nerves has been shown to contribute to nerve bridging.In this study,we used a 10-mm sciatic nerve defect model in rats to determine whether cartilage oligomeric matrix protein enhances the vascularization of injured acellular nerves.The rat nerve defects were treated with acellular nerve grafting（control group） alone or acellular nerve grafting combined with intraperitoneal injection of cartilage oligomeric matrix protein（experimental group）.As shown through two-dimensional imaging,the vessels began to invade into the acellular nerve graft from both anastomotic ends at day 7 post-operation,and gradually covered the entire graft at day 21.The vascular density,vascular area,and the velocity of revascularization in the experimental group were all higher than those in the control group.These results indicate that cartilage oligomeric matrix protein enhances the vascularization of acellular nerves.展开更多
文摘Background:Ischemic retinopathies(IRs)are ocular disorders associated to microvascular degeneration leading to visual impairments and blindness.microRNA(miRNAs)are a family of non-coding RNAs that regulate a wide range of gene expression involved in various biological process such blood vessel development and pathological NV.However,the post-transcriptional modulation of miRs and especially,their specific functions in the eyes during IRs remain to be evaluated.We aim to evaluate the potential role of miR-96 on microvascular degeneration in a rat model of oxygen-induced retinopathy(OIR).Methods:In vivo:next generation sequencing(NSG)was used to perform a complete miRNAs profiling in the retina and choroid from OIR and normoxia(CTL)rats.To evaluate the effects of miR-96 on microvasculature,OIR animals were treated with a miR-96 mimic(1 mg/kg)or a control-miR by intravitreal injection before hyperoxia-exposure(80%O2).Immunostaining analysis of retinal flatmounts and cryosections was used to explore the microvascular effects of miR-96.In vitro:Human Retinal Microvascular Endothelial Cells(HRMVEC)were subjected or not to hyperoxia(80%O2)and transfected with 50 nM of miR-96 mimic or antagomir-96.Angiogenic assay was performed(tube formation and migration)and molecular analysis evaluated by qRT-PCR and western blot.Results:NSG and qRT-PCR analyses identified miR-96 as one of most highly expressed miRNAs in retina and choroid during development.However,miR-96 showed a strong downregulation in OIR rats,and also in HRMVEC subjected to hyperoxia.In HRMVEC,we found that miR-96 regulates positively the expression of the key pro-angiogenic factors VEGF,FGF-2 and ANG-2.To better explore the role of miR-96 on HRMVEC angiogenic activity,we performed a gain/loss of function study.Similarly,to hyperoxia exposure,we observed a robust angiogenic impairment(tube formation and migration)on HMRVEC transfected with an antagomiR-96.Interestingly,overexpression of miR-96 completely recued the basal phenotype of HRMVEC and protected against hyperoxia-induced endothelial dysfunction.In vivo,intravitreal injection of miR-96 mimic(1 mg/kg)in OIR rats significantly restored retinal vascular density and choroidal tightness/sprouting hability.This was accompanied by the restoration in the physiological levels of VEGF,FGF-2 and ANG-2.Conclusions:This is the first study showing that reduced expression of miR-96 in OIR conditions lead to a reduction of VEGF/FGF/ANG-2 signaling,and inneficient post-ischemic revascularization in retinal/choroidal tissues.Intravitreal supplementation of miR-96 using a miR mimic could constitute a novel therapeutic strategy to improve vascular repair in IRs.
基金Supported by the National Natural Science Foundation of China,No.11672197 and No.81702171the Shenzhen Double Chain Project for Innovation and Development Industry supported by the Bureau of Industry and Information Technology of Shenzhen,No.201806081018272960
文摘Stem cells have shown great potential in vascular repair.Numerous evidence indicates that mechanical forces such as shear stress and cyclic strain can regulate the adhesion,proliferation,migration,and differentiation of stem cells via serious signaling pathways.The enrichment and differentiation of stem cells play an important role in the angiogenesis and maintenance of vascular homeostasis.In normal tissues,blood flow directly affects the microenvironment of vascular endothelial cells(ECs);in pathological status,the abnormal interactions between blood flow and vessels contribute to the injury of vessels.Next,the altered mechanical forces are transduced into cells by mechanosensors to trigger the reformation of vessels.This process occurs when signaling pathways related to EC differentiation are initiated.Hence,a deep understanding of the responses of stem cells to mechanical stresses and the underlying mechanisms involved in this process is essential for clinical translation.In this the review,we provide an overview of the role of stem cells in vascular repair,outline the performance of stem cells under the mechanical stress stimulation,and describe the related signaling pathways.
基金supported by Macao Young Scholars Program(AM2020032)Macao Science and Technology Development Fund(0061/2021/A2)and(EF026/ICMS-SHX/2022/SZSTIC).
文摘Traumatic brain injury(TBI)disrupts normal brain function and is associated with high morbidity and fatality rates.TBI is characterized as mild,moderate or severe depending on its severity.The damage may be transient and limited to the dura matter,with only subtle changes in cerebral parenchyma,or life-threatening with obvious focal contusions,hematomas and edema.Blood vessels are often injured in TBI.Even in mild TBI,dysfunctional cerebral vascular repair may result in prolonged symptoms and poor outcomes.Various distinct types of cells participate in vascular repair after TBI.A better understanding of the cellular response and function in vascular repair can facilitate the development of new therapeutic strategies.In this review,we analyzed the mechanism of cerebrovascular impairment and the repercussions following various forms of TBI.We then discussed the role of distinct cell types in the repair of meningeal and parenchyma vasculature following TBI,including endothelial cells,endothelial progenitor cells,pericytes,glial cells(astrocytes and microglia),neurons,myeloid cells(macrophages and monocytes)and meningeal lymphatic endothelial cells.Finally,possible treatment techniques targeting these unique cell types for vascular repair after TBI are discussed.
基金supported by the National Natural Science Foundation of China(No.52073204).
文摘With adjustable amphiphilicity and anionic/cationic charge,biodegradability and biocompatibility,amino acid-based poly(ester amide)s(PEAs)have drawn attention in the research of tissue engineered vascular grafts.In this work,L-phenylalanine-based PEAs with or without L-lysine were synthesized through polycondensation,and ultrafine fibrous grafts consisted of PEAs and poly(ε-caprolactone)(PCL)in given mass ratios were further prepared via blend electrospinning.Surface characterizations by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy confirmed the chemical structure,and the wettability indicated that the prepared PCL/PEAs electrospun membranes exhibited less hydrophobic than PCL.Tensile results showed that the PCL/PEAs membranes possessed suitable mechanical properties,which could meet the requirements of artificial blood vessels.Cell culture and hemolytic tests exhibited that the PCL/PEAs electrospun membranes are biocompatible.In general,the electrospun grafts of PCL/PEAs could be applied for vascular repair.
基金the National Natural Science Foundation of Chinagrant number:81301562 and 81572147。
文摘The exact molecular and cytological mechanism of how glucocorticoids induce vascular repair disorders in glucocorticoid-induced avascular necrosis of the femoral head is still unclear.We used bioinformatical tools for data mining and detected the biological behavior of endothelial cells(ECs)under hypoxia conditions and high dose dexamethasone to reveal the mechanisms above.Six differential expression mi RNAs(DE-miRNAs)were filtered from Gene Expression Omnibus(GEO)database GSE60093 which contained ECs treated with high dose glucocorticoid and control samples.Enrichment and PPI network analyses of the DE-miRNAs target genes showed the most remarkable pathway was HIF-1 signaling pathway and high dose glucocorticoid as a negative regulator of cell differentiation,energy metabolism,migration and cytokines secretion.Glucocorticoids also reduced the activity of autocrine/paracrine via limiting ion channels and transmembrane transporter process.In cytological experiment,HUVECs were divided into four groups:hypoxia group(H),hypoxia+dexamethasone group(HD),dexamethasone group(D),the normal group(N).Cell activity detection and Live/Dead dyeing showed cell activity and the number of live cells in Group H was higher than the other three groups at 24 h after intervention,while cell activity,number and proportion of live cells in HD group were worst.Cytoskeleton staining showed HD group met cytoskeleton form disorders.The scratch assay showed cell migration ability of Group H was strongest while cell migration ability of the HD group was worst.MIF expression in HD group showed a trend of bimodal,the peak of VEGF-A secretion lagged behind the MIF’s.Expression of MIF and VEGF-A in the HD group were low.High dose dexamethasone suppressed the active response of ECs to hypoxia stimulation via directly inhibiting the expression of MIF and interdicting autocrine/paracrine mechanism.We infered that the treatment with high dose glucocorticoid would inhibit neo-angiogenesis under hypoxia followed by aggravating hypoxia/ischemia and osteonecrosis.
基金Supported by grants from the National Institutes of Health(R01 AR050211P30 AR057235)
文摘Bone is a highly vascularized tissue, although this aspect of bone is often overlooked. In this article, the importance of blood flow in bone repair and regeneration will be reviewed. First, the skeletal vascular anato- my, with an emphasis on long bones, the distinct mechanisms for vascularizing bone tissue, and methods for remodeling existing vasculature are discussed. Next, techniques for quantifying bone blood flow are briefly summarized. Finally, the body of experimental work that demonstrates the role of bone blood flow in fracture healing, distraction osteogenesis, osteoporosis, disuse osteopenia, and bone grafting is examined. These results illustrate that adequate bone blood flow is an important clinical consideration, particularly during bone regeneration and in at-risk patient groups.
基金supported by the Specialized Research Fund for Science and Technology Plan of Guangdong Province in China,No.201313060300007the National High-Technology Research and Development Program of China(863 Program),No.2012AA020507+2 种基金the National Basic Research Program of China(973 Program),No.2014CB542201the Doctoral Program of Higher Education of China,No.20120171120075Doctoral Start-up Project of the Natural Science Foundation of Guangdong Province in China,No.S201204006336 and 1045100890100590
文摘Vascularization of acellular nerves has been shown to contribute to nerve bridging.In this study,we used a 10-mm sciatic nerve defect model in rats to determine whether cartilage oligomeric matrix protein enhances the vascularization of injured acellular nerves.The rat nerve defects were treated with acellular nerve grafting（control group） alone or acellular nerve grafting combined with intraperitoneal injection of cartilage oligomeric matrix protein（experimental group）.As shown through two-dimensional imaging,the vessels began to invade into the acellular nerve graft from both anastomotic ends at day 7 post-operation,and gradually covered the entire graft at day 21.The vascular density,vascular area,and the velocity of revascularization in the experimental group were all higher than those in the control group.These results indicate that cartilage oligomeric matrix protein enhances the vascularization of acellular nerves.
