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Background: One of the most severe consequences of ageing is cognitive decline, which is associated with dysfunction of the brain microvasculature. Thus, repairing the brain vasculature could result in healthier brain function. Methods: To better understand the potential beneficial effect of endothelial progenitor cells (EPCs) in vascular repair, we studied the adhesion and integration of EPCs using the early embryonic mouse aorta–gonad–mesonephros – MAgEC 10.5 endothelial cell line. The EPC interaction with brain microvasculature was monitored ex vivo and in vivo using epifluorescence, laser confocal and two-photon microscopy in healthy young and old animals. The effects of senolysis, EPC activation and ischaemia (two-vessel occlusion model) were analysed in BALB/c and FVB/Ant: TgCAG-yfp_sb #27 mice. Results: MAgEC 10.5 cells rapidly adhered to brain microvasculature and some differentiated into mature endothelial cells (ECs). MAgEC 10.5-derived endothelial cells integrated into microvessels, established tight junctions and co-formed vessel lumens with pre-existing ECs within five days. Adhesion and integration were much weaker in aged mice, but were increased by depleting senescent cells using abt-263 or dasatinib plus quercetin. Furthermore, MAgEC 10.5 cell adhesion to and integration into brain vessels were increased by ischaemia and by pre-activating EPCs with TNFα. Conclusions: Combining progenitor cell therapy with senolytic therapy and the prior activation of EPCs are promising for improving EPC adhesion to and integration into the cerebral vasculature and could help rejuvenate the ageing brain. [ABSTRACT FROM AUTHOR]

The increasing burden of vascular dysfunction on healthcare systems worldwide results in higher morbidity and mortality rates across pathologies, including cardiovascular diseases. Vasculopathy is suggested to be caused by the dysregulation of vascular niches, a microenvironment of vascular structures comprising anatomical structures, extracellular matrix components, and various cell populations. These elements work together to ensure accurate control of the vascular network. In recent years, autophagy has been recognized as a crucial regulator of the vascular microenvironment responsible for maintaining basic cell functions such as proliferation, differentiation, replicative senescence, and apoptosis. Experimental studies indicate that autophagy activation can be enhanced or inhibited in various pathologies associated with vascular dysfunction, suggesting that autophagy plays both beneficial and detrimental roles. Here, we review and assess the principles of autophagy organization and regulation in non-tumor vascular niches. Our analysis focuses on significant figures in the vascular microenvironment, highlighting the role of autophagy and summarizing evidence that supports the systemic or multiorgan nature of the autophagy effects. Finally, we discuss the critical organizational and functional aspects of the vasculogenic niche, specifically in relation to autophagy. The resulting dysregulation of the vascular microenvironment contributes to the development of vascular dysfunction. [ABSTRACT FROM AUTHOR]

Background: Exosomes produced by mesenchymal stem cells (MSCs) have vascular generative properties and are considered new effective candidates for the treatment of bone defects as alternatives to cell therapy. Improving the pro-regenerative function and efficacy of exosomes has been a popular research topic in the field of orthopaedics. Methods: We prepared mesoporous bioactive glass (mBG) microspheres via the template method. The ionic products of mBGs used to treat MSCs were extracted, and the effects of exosomes secreted by MSCs on osteoblast (OB) and macrophage (MP) behaviour and bone defect repair were observed in vivo (Micro-CT, H&E, Masson, and immunofluorescence staining for BMP2, COL1, VEGF, CD31, CD163, and iNOS). Results: The mBG spheres were successfully prepared, and the Exo-mBG were isolated and extracted. Compared with those in the blank and Exo-Con groups, the proliferation and osteogenic differentiation of OBs in the Exo-mBG group were significantly greater. For example, on Day 7, OPN gene expression in the Ctrl-Exo group was 3.97 and 2.83 times greater than that in the blank and Exo-mBG groups, respectively. In a cranial defect rat model, Exo-mBG promoted bone tissue healing and angiogenesis, increased M2 macrophage polarisation and inhibited M1 macrophage polarisation, as verified by micro-CT, H&E staining, Masson staining and immunofluorescence staining. These effects may be due to the combination of a higher silicon concentration and a higher calcium-to-phosphorus ratio in the mBG ionic products. Conclusion: This study provides insights for the application of exosomes in cell-free therapy and a new scientific basis and technical approach for the utilisation of MSC-derived exosomes in bone defect repair. The translational potential of this article: Our study demonstrated that exosomes produced by mBG-stimulated MSCs have excellent in vitro and in vivo bone-enabling and immunomodulatory functions and provides insights into the use of exosomes in clinical cell-free therapies.

The significance of collagen and vascular in skin augmentation have been recognized in recent years. However, current skin tissue fillers, e.g. hyaluronic acid (HA) or HA-based hydrogel, fail to meet the perfect augmentation requirements due to their inadequate long-term support effect and the lack of tissue-inducing activity. Herein, an injectable skin filler containing hyaluronic acid (HA) hydrogel and lithium calcium silicate (LCS, Li2Ca4Si4O13) bioceramic microspheres was developed for skin tissue fillers, owing to the excellent biological function of silicate bioceramics. The HA-LCS fillers could be easily injected through a tiny standard medical needle (27 G) with force of less than 36 N, and showed good biocompatibility both in vitro and in vivo. Furthermore, the bioactive ions released from HA-LCS fillers significantly enhanced the expression of vascularization-related genes and collagen-related genes. Importantly, the HA-LCS fillers not only stimulated the regeneration of mature blood vessels, but also promoted collagen secretion in dermal skin and filling area. This study not only presented an injectable filler with enhanced regeneration of blood vessels and collagen, but also provided a new strategy for developing tissue-induced fillers based on bioactive components of silicate bioceramics.

Abstract Background A favorable regenerative microenvironment is essential for peripheral nerve regeneration. Neural tissue-specific extracellular matrix (ECM) is a natural material that helps direct cell behavior and promote axon regeneration. Both bone marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived mesenchymal stem cells (ADSCs) transplantation are effective in repairing peripheral nerve injury (PNI). However, there is no study that characterizes the in vivo microenvironmental characteristics of these two MSCs for the early repair of PNI when combined with neural tissue-derived ECM materials, i.e., acellular nerve allograft (ANA). Methods In order to investigate biological characteristics, molecular mechanisms of early stage, and effectiveness of ADSCs- or BMSCs-injected into ANA for repairing PNI in vivo, a rat 10 mm long sciatic nerve defect model was used. We isolated primary BMSCs and ADSCs from bone marrow and adipose tissue, respectively. First, to investigate the in vivo response characteristics and underlying molecular mechanisms of ANA combined with BMSCs or ADSCs, eighty-four rats were randomly divided into three groups: ANA group, ANA+BMSC group, and ANA+ADSC group. We performed flow cytometry, RT-PCR, and immunofluorescence staining up to 4 weeks postoperatively. To further elucidate the underlying molecular mechanisms, changes in long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) were systematically investigated using whole transcriptome sequencing. We then constructed protein–protein interaction networks to find 10 top ranked hub genes among differentially expressed mRNAs. Second, in order to explore the effectiveness of BMSCs and ADSCs on neural tissue-derived ECM materials for repairing PNI, sixty-eight rats were randomized into four groups: ANA group, ANA+BMSC group, ANA+ADSC group, and AUTO group. In the ANA+BMSC and ANA+ADSC groups, ADSCs/BMSCs were equally injected along the long axis of the 10-mm ANA. Then, we performed histological and functional assessments up to 12 weeks postoperatively. Results The results of flow cytometry and RT-PCR showed that ANA combined with BMSCs exhibited more significant immunomodulatory effects, as evidenced by the up-regulation of interleukin (IL)-10, down-regulation of IL-1β and tumor necrosis factor-alpha (TNF-α) expression, promotion of M1-type macrophage polarization to M2-type, and a significant increase in the number of regulatory T cells (Tregs). ANA combined with ADSCs exhibited more pronounced features of pro-myelination and angiogenesis, as evidenced by the up-regulation of myelin-associated protein gene (MBP and MPZ) and angiogenesis-related factors (TGF-β, VEGF). Moreover, differentially expressed genes from whole transcriptome sequencing results further indicated that ANA loaded with BMSCs exhibited notable immunomodulatory effects and ANA loaded with ADSCs was more associated with angiogenesis, axonal growth, and myelin formation. Notably, ANA infused with BMSCs or ADSCs enhanced peripheral nerve regeneration and motor function recovery with no statistically significant differences. Conclusions This study revealed that both ANA combined with BMSCs and ADSCs enhance peripheral nerve regeneration and motor function recovery, but their biological characteristics (mainly including immunomodulatory effects, pro-vascular regenerative effects, and pro-myelin regenerative effects) and underlying molecular mechanisms in the process of repairing PNI in vivo are different, providing new insights into MSC therapy for peripheral nerve injury and its clinical translation.

Background: Bone marrow mesenchymal stem cells (BMSC)-derived exosomes (Exos) are important in promoting bone and vascular regeneration. Antler blood (ALB) is a valuable traditional Chinese medicine with potent regenerative effects. However, there is still a lack of clarity regarding the relationship between ALB and BMSC-Exos. Methods: Primary BMSCs were isolated from SD Rats, and BMSC-derived Exos (BMSC-Exos) were harvested and identified accordingly. ALB was treated with the solution contained pepsin and hydrochloric acid to simulated gastrointestinal digestion in vitro. Furthermore, the liquid chromatography-mass spectrometry (LC-MS) was performed to determine the components of digested ALB. Moreover, ALB was utilized to intervene on BMSCs to produce specialized Exos (Exos-ALB), of which the angiogenesis functions were detected both in vitro and in vivo. For the potential mechanism, both high-throughput sequencing and proteomics were performed. Results: The main components of ALB consist of amino acids and peptides. Both ALB and BMSC-Exos exhibited significant promotion of bone and blood vessel formation, respectively. Moreover, ALB and BMSC-Exos could increase the expression of BMP-2, RUNX2, and ALP, but reduce the Osteopontin (OPN) expression. Notably, Exos-ALB exhibited the strongest performance in these functions, whereas the presence of miR-21-5p inhibitor can partially counteract the effects of Exos-ALB. The proteomics reveal differential genes associated with bone minimization, angiogenesis, osteoblast differentiation, vesicle-mediated transport, and the Wnt signaling pathway. Conclusion: ALB enhances the ability of BMSCs-derived Exos to promote bone and vascular regeneration, which may be related to the up-regulation of miR-21-5p.

BACKGROUND: Vascular regeneration, as one of the crucial repair processes after its onset, necessitates visual analysis between the two. OBJECTIVE: To analyze the literature on ischemic stroke and vascular regeneration in the past decade using bibliometrics and sort out the current status, hotspots, and future research trends in this field. METHODS: We used a bibliometric approach to search the Web of Science database for literature on ischemic stroke and vascular regeneration published between January 2011 and May 2023. The obtained data were systematically analyzed using the VOSviewer visualization software to identify the number of articles, countries, keywords, institutions, authors, citations, and trends. RESULTS AND CONCLUSION: We searched and selected 1 484 articles and found that the relationship between ischemic stroke and vascular regeneration has emerged as a research hotspot in the cerebrovascular field, with the number of published articles continuing to rise. Most of these articles were authored by institutions from China and the United States. Shanghai Jiao Tong University was the most cited institution. The most influential author was Hermann DM, whose article had been cited 1 003 times. The current hot research topics in the field include extracellular vesicles, microRNAs and mesenchymal stem cells, which are being studied for their correlations with relevant diseases. To conclude, the bibliometric analysis provides a visual analysis of ischemic stroke and vascular regeneration, which is found to be an emerging focus as well as a valuable reference for future trends and highlights in ischemic stroke and vascular regeneration. [ABSTRACT FROM AUTHOR]

CNS diseases associated with compromised blood supply and/or vascular integrity are one of the leading causes of mortality and disability in adults worldwide and are also among 10 most common causes of death in children. Angiogenesis is an essential element of regeneration processes upon nervous tissue damage and can play a crucial role in neuroprotection. Here we review the features of cerebral vascular regeneration after ischemic stroke, including the complex interactions between endothelial cells and other brain cell types (neural stem cells, astrocytes, microglia, and oligodendrocytes). The mechanisms of reciprocal influence of angiogenesis and neurogenesis, the role of astrocytes in the formation of the blood—brain barrier, and roles of microglia and oligodendrocytes in vascular regeneration are discussed. Understanding the mechanisms of angiogenesis regulation in CNS is of critical importance for the development of new treatments of neurovascular pathologies. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline-recommended therapies for the management of type 2 diabetes (T2D), atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. We previously observed in people living with T2D and coronary artery disease that circulating vascular regenerative (VR) progenitor cell content increased following 6-mo use of the SGLT2 inhibitor empagliflozin. In this post hoc subanalysis of the ORIGINS-RCE CardioLink-13 study (ClinicalTrials.gov Identifier NCT05253521), we analyzed the circulating VR progenitor cell content of 92 individuals living with T2D, among whom 20 were on a GLP-1RA, 42 were on an SGLT2 inhibitor but not a GLP-1RA, and 30 were on neither of these vascular protective therapies. In the GLP-1RA group, the mean absolute count of circulating VR progenitor cells defined by high aldehyde dehydrogenase (ALDH) activity (ALDHhiSSClow) and VR progenitor cells further characterized by surface expression of the proangiogenic marker CD133 (ALDHhiSSClowCD133+) was higher than the group receiving neither a GLP-1RA nor an SGLT2 inhibitor (P = 0.02) and comparable with that in the SGLT2 inhibitor group (P = 0.25). The absolute count of proinflammatory, granulocyte-restricted precursor cells (ALDHhiSSChi) was significantly lower in the GLP-1RA group compared with the group on neither therapy (P = 0.031). Augmented vessel repair initiated by VR cells with previously documented proangiogenic activity, alongside a reduction in systemic, granulocyte precursor-driven inflammation, may represent novel mechanisms responsible for the cardiovascular-metabolic benefits of GLP-1RA therapy. Prospective, randomized clinical trials are now warranted to establish the value of recovering circulating VR progenitor cell content with blood vessel regenerative functions. NEW & NOTEWORTHY: In this post hoc subanalysis of 92 individuals living with T2D and at high cardiovascular risk, the authors summarize the differences in circulating vascular regenerative (VR) progenitor cell content between those on GLP-1RA therapy, on SGLT2 inhibitor without GLP-1RA therapy, and on neither therapy. Those on GLP-1RA therapy demonstrated greater circulating VR progenitor cell content and reduced proinflammatory granulocyte precursor content. These results offer novel mechanistic insights into the cardiometabolic benefits associated with GLP-1RA therapy. [ABSTRACT FROM AUTHOR]

Background: A favorable regenerative microenvironment is essential for peripheral nerve regeneration. Neural tissue-specific extracellular matrix (ECM) is a natural material that helps direct cell behavior and promote axon regeneration. Both bone marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived mesenchymal stem cells (ADSCs) transplantation are effective in repairing peripheral nerve injury (PNI). However, there is no study that characterizes the in vivo microenvironmental characteristics of these two MSCs for the early repair of PNI when combined with neural tissue-derived ECM materials, i.e., acellular nerve allograft (ANA). Methods: In order to investigate biological characteristics, molecular mechanisms of early stage, and effectiveness of ADSCs- or BMSCs-injected into ANA for repairing PNI in vivo, a rat 10 mm long sciatic nerve defect model was used. We isolated primary BMSCs and ADSCs from bone marrow and adipose tissue, respectively. First, to investigate the in vivo response characteristics and underlying molecular mechanisms of ANA combined with BMSCs or ADSCs, eighty-four rats were randomly divided into three groups: ANA group, ANA+BMSC group, and ANA+ADSC group. We performed flow cytometry, RT-PCR, and immunofluorescence staining up to 4 weeks postoperatively. To further elucidate the underlying molecular mechanisms, changes in long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) were systematically investigated using whole transcriptome sequencing. We then constructed protein–protein interaction networks to find 10 top ranked hub genes among differentially expressed mRNAs. Second, in order to explore the effectiveness of BMSCs and ADSCs on neural tissue-derived ECM materials for repairing PNI, sixty-eight rats were randomized into four groups: ANA group, ANA+BMSC group, ANA+ADSC group, and AUTO group. In the ANA+BMSC and ANA+ADSC groups, ADSCs/BMSCs were equally injected along the long axis of the 10-mm ANA. Then, we performed histological and functional assessments up to 12 weeks postoperatively. Results: The results of flow cytometry and RT-PCR showed that ANA combined with BMSCs exhibited more significant immunomodulatory effects, as evidenced by the up-regulation of interleukin (IL)-10, down-regulation of IL-1β and tumor necrosis factor-alpha (TNF-α) expression, promotion of M1-type macrophage polarization to M2-type, and a significant increase in the number of regulatory T cells (Tregs). ANA combined with ADSCs exhibited more pronounced features of pro-myelination and angiogenesis, as evidenced by the up-regulation of myelin-associated protein gene (MBP and MPZ) and angiogenesis-related factors (TGF-β, VEGF). Moreover, differentially expressed genes from whole transcriptome sequencing results further indicated that ANA loaded with BMSCs exhibited notable immunomodulatory effects and ANA loaded with ADSCs was more associated with angiogenesis, axonal growth, and myelin formation. Notably, ANA infused with BMSCs or ADSCs enhanced peripheral nerve regeneration and motor function recovery with no statistically significant differences. Conclusions: This study revealed that both ANA combined with BMSCs and ADSCs enhance peripheral nerve regeneration and motor function recovery, but their biological characteristics (mainly including immunomodulatory effects, pro-vascular regenerative effects, and pro-myelin regenerative effects) and underlying molecular mechanisms in the process of repairing PNI in vivo are different, providing new insights into MSC therapy for peripheral nerve injury and its clinical translation. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) are increasingly recognized for their regenerative potential. However, their clinical application is hindered by their inherent variability, which is influenced by various factors, such as the tissue source, culture conditions, and passage number. Methods: MSCs were sourced from clinically relevant tissues, including adipose tissue-derived MSCs (ADMSCs, n = 2), chorionic villi-derived MSCs (CMMSCs, n = 2), amniotic membrane-derived MSCs (AMMSCs, n = 3), and umbilical cord-derived MSCs (UCMSCs, n = 3). Passages included the umbilical cord at P0 (UCMSCP0, n = 2), P3 (UCMSCP3, n = 2), and P5 (UCMSCP5, n = 2) as well as the umbilical cord at P5 cultured under low-oxygen conditions (UCMSCP5L, n = 2). Results: We observed that MSCs from different tissue origins clustered into six distinct functional subpopulations, each with varying proportions. Notably, ADMSCs exhibited a higher proportion of subpopulations associated with vascular regeneration, suggesting that they are beneficial for applications in vascular regeneration. Additionally, CMMSCs had a high proportion of subpopulations associated with reproductive processes. UCMSCP5 and UCMSCP5L had higher proportions of subpopulations related to female reproductive function than those for earlier passages. Furthermore, UCMSCP5L, cultured under low-oxygen (hypoxic) conditions, had a high proportion of subpopulations associated with pro-angiogenic characteristics, with implications for optimizing vascular regeneration. Conclusions: This study revealed variation in the distribution of MSC subpopulations among different tissue sources, passages, and culture conditions, including differences in functions related to vascular and reproductive system regeneration. These findings hold promise for personalized regenerative medicine and may lead to more effective clinical treatments across a spectrum of medical conditions. [ABSTRACT FROM AUTHOR]

In the case of wounds with exposed bone, it is essential to provide not only scaffolds with sufficient mechanical strength for protection, but also environments that are conducive to the regeneration of tissues and blood vessels. Despite the excellent biocompatibility and biodegradability of collagen and chondroitin sulfate, they display poor mechanical strength and rapid degradation rates. In contrast to previous methodologies that augmented the mechanical properties of biomaterials through the incorporation of additional substances, this investigation exclusively enhanced the mechanical strength of collagen/chondroitin sulfate scaffolds by modulating collagen concentrations. Furthermore, platelet-rich plasma (PRP) was employed to establish optimal conditions for vascular and tissue regeneration at the wound site. High-concentration collagen/chondroitin sulfate (H C-S) scaffolds were synthesized using high-speed centrifugation and combined with PRP, and their effects on endothelial cell proliferation were assessed. A porcine model of bone-exposed wounds was developed to investigate the healing effects and mechanisms. The experimental results indicated that scaffolds with increased collagen concentration significantly enhanced both tensile and compressive moduli. The combination of H C-S scaffolds with PRP markedly promoted endothelial cell proliferation. In vivo experiments demonstrated that this combination significantly accelerated the healing of porcine bone-exposed wounds and promoted vascular regeneration. This represents a promising strategy for promoting tissue regeneration that is worthy of further exploration and clinical application.

Background Mesenchymal stem cells (MSCs) are increasingly recognized for their regenerative potential. However, their clinical application is hindered by their inherent variability, which is influenced by various factors, such as the tissue source, culture conditions, and passage number. Methods MSCs were sourced from clinically relevant tissues, including adipose tissue-derived MSCs (ADMSCs, n = 2), chorionic villi-derived MSCs (CMMSCs, n = 2), amniotic membrane-derived MSCs (AMMSCs, n = 3), and umbilical cord-derived MSCs (UCMSCs, n = 3). Passages included the umbilical cord at P0 (UCMSCP0, n = 2), P3 (UCMSCP3, n = 2), and P5 (UCMSCP5, n = 2) as well as the umbilical cord at P5 cultured under low-oxygen conditions (UCMSCP5L, n = 2). Results We observed that MSCs from different tissue origins clustered into six distinct functional subpopulations, each with varying proportions. Notably, ADMSCs exhibited a higher proportion of subpopulations associated with vascular regeneration, suggesting that they are beneficial for applications in vascular regeneration. Additionally, CMMSCs had a high proportion of subpopulations associated with reproductive processes. UCMSCP5 and UCMSCP5L had higher proportions of subpopulations related to female reproductive function than those for earlier passages. Furthermore, UCMSCP5L, cultured under low-oxygen (hypoxic) conditions, had a high proportion of subpopulations associated with pro-angiogenic characteristics, with implications for optimizing vascular regeneration. Conclusions This study revealed variation in the distribution of MSC subpopulations among different tissue sources, passages, and culture conditions, including differences in functions related to vascular and reproductive system regeneration. These findings hold promise for personalized regenerative medicine and may lead to more effective clinical treatments across a spectrum of medical conditions.

The article explores the vascular regenerative benefits of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, particularly focusing on semaglutide, in individuals with type 2 diabetes and high cardiovascular risk. Topics include the increase in vascular regenerative progenitor cell content associated with GLP-1R agonist treatment, the comparison with sodium-glucose cotransporter-2 (SGLT2) inhibitors, and the broader cardioprotective effects of GLP-1R agonists beyond weight loss.

Objective：To discuss the effect of ligustilide on the cardiac function and angiogenesis in the rats with heart failure, and to clarify its regulatory effect on protein kinase D1 (PKD1) /hypoxia-inducible factor-1α (HIF-1α) /vascular endothelial growth factor (VEGF) pathway. Methods：The SD rats were randomly divided into sham operation group, model group, ligustilide group, PKD1/HIF-1α/VEGF signaling pathway inhibitor CID755673 (CID) group, and ligustilide+CID group. The heart failure rat model was established by ligation of the left anterior descending coronary artery. The rats in ligustilide group were injected intravenously with 20 mg·kg－1 ligustilide, the rats in CID group were injected intraperitoneally with 50 mg·kg－1 CID, and the rats in ligustilide+CID group were injected intraperitoneally with 50 mg·kg－1 CID followed by intravenous injection of 20 mg·kg－1 ligustilide, once per day for 4 consecutive weeks. The cardiac function indexes of the rats in various groups were detected by echocardiography；the percentages of myocardial infarction areas of the rats in various groups were detected by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining； the pathomorphology of myocardium tissue of the rats in various groups was observed by HE staining； the expression levels of PKD1, HIF-1α, CD31, and VEGF mRNA and proteins in ischemic area of myocardium tissue of the rats in various groups were detected by real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting methods. Results：Compared with sham operation group, the rats in model group and CID group had altered myocardial cell morphology, increased intercellular gaps, disorganized arrangement, visible muscle fiber breaks and inflammatory cell infiltration； the rats in ligustilide group and ligustilide+CID group had relatively orderly myocardial fiber arrangement, fewer myocardial fiber breaks and decreased number of inflammatory cells. Compared with sham operation group, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) of the rats in model group were decreased (P<0. 05), the left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD) were increased (P<0. 05), and the expression levels of PKD1, HIF-1α, CD31, and VEGF mRNA and proteins in myocardium tissue were decreased (P<0. 05) . Compared with model group, the LVEF and LVFS of the rats in ligustilide group were increased (P<0. 05), the LVESD and LVEDD were decreased (P<0. 05), the percentage of myocardium infarction area was decreased (P<0. 05), and the expression levels of PKD1, HIF-1α, CD31, and VEGF mRNA and proteins in myocardium tissue were increased (P< 0. 05) ； compared with model group, the LVEF and LVFS of the rats in CID group were decreased (P< 0. 05), the LVESD and LVEDD were increased (P<0. 05), the percentage of myocardium infarction area was increased (P<0. 05), and the expression levels of PKD1, HIF-1α, CD31, and VEGF mRNA and proteins in myocardium tissue were decreased (P<0. 05) ； compared with ligustilide group, the LVEF and LVFS of the rats in ligustilide+CID group were decreased (P<0. 05), the LVESD and LVEDD were increased (P<0. 05), the percentage of myocardium infarction area was increased (P<0. 05), and the expression levels of PKD1, HIF-1α, CD31, and VEGF mRNA and proteins in myocardium tissue were decreased (P<0. 05) ；compared with CID group, the LVEF and LVFS of the rats in ligustilide+CID group were increased (P<0. 05), the LVESD and LVEDD were decreased (P<0. 05), the percentage of myocardium infarction area was decreased (<0. 05), and the expression levels of PKD1, HIF-1α, CD31, and VEGF mRNA and proteins in myocardium tissue were increased （P<0. 05）. Conclusion : Ligustilide can promote the angiogenesis, reduce the myocardium infarction area， and improve the cardiac function in the rats with heart failure; it works through activation of the PKD1/HIF-1α/VEGF pathway. [ABSTRACT FROM AUTHOR]

The proper regeneration of vessel anastomoses in microvascular surgery is crucial for surgical safety. Pituitary adenylate cyclase-activating polypeptide (PACAP) can aid healing by decreasing inflammation, apoptosis and oxidative stress. In addition to hematological and hemorheological tests, we examined the biomechanical and histological features of vascular anastomoses with or without PACAP addition and/or using a hemostatic sponge (HS). End-to-end anastomoses were established on the right femoral arteries of rats. On the 21st postoperative day, femoral arteries were surgically removed for evaluation of tensile strength and for histological and molecular biological examination. Effects of PACAP were also investigated in tissue culture in vitro to avoid the effects of PACAP degrading enzymes. Surgical trauma and PACAP absorption altered laboratory parameters; most notably, the erythrocyte deformability decreased. Arterial wall thickness showed a reduction in the presence of HS, which was compensated by PACAP in both the tunica media and adventitia in vivo. The administration of PACAP elevated these parameters in vitro. In conclusion, the application of the neuropeptide augmented elastin expression while HS reduced it, but no significant alterations were detected in collagen type I expression. Elasticity and tensile strength increased in the PACAP group, while it decreased in the HS decreased. Their combined use was beneficial for vascular regeneration. [ABSTRACT FROM AUTHOR]

Objective To investigate the therapeutic effect of liraglutide on acute cerebral infarction (ACI) in patients with type 2 diabetes mellitus (T2DM), and its effect on neurological function and serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Methods A total of 160 patients with ACI accompanied by T2DM admitted to Haikou People's Hospital from March 2020 to March 2022 were randomly divided into observation group and control group (n=80, each). Both groups of patients were given routine treatment for ACI. On this basis, the control group was treated with insulin aspart and insulin glargine, while the observation group was treated with liraglutide and insulin glargine. Both groups received continuous treatment for 3 months. In addition to clinical efficacy, fasting blood glucose (FBG) before and after treatment, 2-hour postprandial blood glucose (2hPG), hemoglobin A1c (HbA1c), insulin resistance index (HOMA-IR), National Institutes of Health Stroke Scale (NIHSS), and modified Rankin Scale (mRS) scores of two groups of patients was compared. Enzyme linked immunosorbent assay was used to detect the levels of serum VEGF and bFGF before treatment and after 1 and 3 months of treatment in both groups. Results After treatment, the levels of FBG, bFGF, HbA1c, HOMA-IR, and the scores of NIHSS and mRS in the observation group decreased compared to those before treatment, and the above indicators levels in the observation group were significantly lower than those in the control group (P＜0.05). The total clinical effective rate of the observation group was significantly higher than that of the control group ［95.00%(76/80) vs 83.75%(67/80), χ2=5.331, P=0.021］. After treatment, the levels of serum VEGF and bFGF showed a gradual downward trend in both groups (P＜0.05). After 1 month and 3 months of treatment, the serum VEGF and bFGF levels in the observation group were significantly higher than those in the control group (P＜0.05). Conclusion Liraglutide combined with insulin glargine can effectively control blood sugar, reduce insulin resistance, alleviate neurological damage, upregulate serum VEGF and bFGF levels, and improve clinical efficacy in T2DM patients with ACI.

Tissue-resident vascular endothelial stem cells (VESCs), marked by expression of CD157, possess long-term repopulating potential and contribute to vascular regeneration and homeostasis in mice. Stem cell exhaustion is regarded as one of the hallmarks of aging and is being extensively studied in several types of tissue-resident stem cells; however, how aging affects VESCs has not been clarified yet. In the present study, we isolated VESCs from young and aged mice to compare their potential to differentiate into endothelial cells in vitro and in vivo. Here, we report that the number of liver endothelial cells (ECs) including VESCs was lower in aged (27–28 month-old) than young (2–3 month-old) mice. In vitro culture of primary VESCs revealed that the potential to generate ECs is impaired in aged VESCs isolated from liver and lung relative to young VESCs. Orthotopic transplantation of VESCs showed that aged VESCs and their progeny expand less efficiently than their young counterparts when transplanted into aged mice, but they are equally functional in young recipients. Gene expression analysis indicated that inflammatory signaling was more activated in aged ECs including VESCs. Using single-cell RNA sequencing data from the Tabula Muris Consortium, we show that T cells and monocyte/macrophage lineage cells including Kupffer cells are enriched in the aged liver. These immune cells produce IL-1β and several chemokines, suggesting the possible involvement of age-associated inflammation in the functional decline of VESCs with age. [ABSTRACT FROM AUTHOR]

Abstract Extensive efforts have been made to achieve vascular regeneration accompanying tissue repair for treating vascular dysfunction-associated diseases. Recent advancements in stem cell biology and cell reprogramming have opened unforeseen opportunities to promote angiogenesis in vivo and generate autologous endothelial cells (ECs) for clinical use. We have, for the first time, identified a unique endothelial-specific transcription factor, ETV2/ER71, and revealed its essential role in regulating endothelial cell generation and function, along with vascular regeneration and tissue repair. Furthermore, we and other groups have demonstrated its ability to directly reprogram terminally differentiated non-ECs into functional ECs, proposing ETV2/ER71 as an effective therapeutic target for vascular diseases. In this review, we discuss the up-to-date status of studies on ETV2/ER71, spanning from its molecular mechanism to vasculo-angiogenic role and direct cell reprogramming toward ECs. Furthermore, we discuss future directions to deploy the clinical potential of ETV2/ER71 as a novel and potent target for vascular disorders such as cardiovascular disease, neurovascular impairment and cancer.

Background: The cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, is predominantly produced by the choroid plexus of the ventricle. Although CSF-derived extracellular vesicles (CSF-EVs) may be utilized as diagnostic and prognostic indicators for illnesses of the central nervous system (CNS), it is uncertain if CSF-EVs may have an impact on neurological function after spinal cord injury (SCI). Methods: Here, we isolated EVs using ultracentrifugation after extracting CSF from Bama miniature pigs. We then combined CSF-EVs with hydrogel and put it on the spinal cord's surface. To determine if CSF-EVs had an impact on mice's neurofunctional recovery, behavioral evaluations were employed. Both in vitro and in vivo, the effect of CSF-EVs on angiogenesis was assessed. We investigated whether CSF-EVs stimulated the PI3K/AKT pathway to alter angiogenesis using the PI3K inhibitor LY294002. Results: CSF-EVs were successfully isolated and identified by transmission electron microscope (TEM), nano-tracking analysis (NTA), and western blot. CSF-EVs could be ingested by vascular endothelial cells as proved by in vivo imaging and immunofluorescence. We demonstrated that CSF-EVs derived from pigs with SCI (SCI-EVs) showed a better effect on promoting vascular regeneration as compared to CSF-EVs isolated from pigs receiving laminectomy (Sham-EVs). Behavioral assessments demonstrated that SCI-EVs could dramatically enhance motor and sensory function in mice with SCI. Western blot analysis suggested that SCI-EVs promote angiogenesis by activating PI3K/AKT signaling pathway, and the pro-angiogenetic effect of SCI-EVs was attenuated by the application of the LY294002 (PI3K inhibitor). Conclusion: Our study revealed that CSF-EVs could enhance vascular regeneration by activating the PI3K/AKT pathway, hence improving motor function recovery after SCI, which may offer potential novel therapeutic options for acute SCI. The translational potential of this article: This study demonstrated the promotion of vascular regeneration and neurological function of CSF-derived exosomes, which may provide a potential therapeutic approach for the treatment of spinal cord injury.

The inertness of synthetic polymer materials and the insufficient mechanical strength of reprocessed decellularized extracellular matrix (dECM) limited their promotive efforts on tissue regeneration. Here, we prepared a hybrid scaffold composed of PCL microfibers and human placental extracellular matrix (pECM) nanofibers by co-electrospinning, which was grafted with heparin and further absorbed with IL-4. The hybrid scaffold with improved hemocompatibility firstly switched macrophages to anti-inflammatory phenotype (increased by 18.1%) and then promoted migration, NO production, tube formation of endothelial cells (ECs), and migration and maturation of vascular smooth muscle cells (VSMCs), and ECM deposition in vitro and in vivo. ECs coverage rate increased by 8.6% and the thickness of the smooth muscle layer was 1.8 times more than PCL grafts at 12 wks. Our study realized the complementary advantages of synthetic polymer materials and dECM materials, and opened intriguing perspectives for the design and construction of small-diameter vascular grafts (SDVGs) and immune-regulated materials for other tissue regeneration.

Excessive inflammation, bacterial infection, and blocked angiogenesis make diabetic wound healing challenging. Multifunctional wound dressings have several advantages in diabetic wound healing. In addition, the pH regulation of the microenvironment is shown to be a key factor that promotes skin regeneration through cellular immune regulation. However, few reports have focused on the development of functional dressings with the ability to regulate the pH microenvironment and promote diabetic wound healing. This study presents a novel approach for regulating the pH microenvironment of diabetic wound sites using a glycopeptide‐based hydrogel consisting of modified hyaluronic acid and poly(6‐aminocaproic acid). This hydrogel forms a network through Schiff base interactions and metal complexation, which suppresses inflammation and accelerates angiogenesis during wound healing. Hydrogels not only have adequate mechanical properties and self‐healing ability but can also support tissue adhesion. They can also promote the secretion of inducible cAMP early repressor, which promotes the polarization of macrophages toward the M2 type. The in vivo results confirm that hydrogel promotes diabetic wound repair and skin regeneration by exerting rapid anti‐inflammatory effects and promoting angiogenesis. Therefore, this hydrogel system represents an effective strategy for treating diabetic wounds. [ABSTRACT FROM AUTHOR]

Chitosan hydrogels have a wide range of applications in tissue engineering scaffolds, mainly due to the advantages of their chemical and physical properties. This review focuses on the application of chitosan hydrogels in tissue engineering scaffolds for vascular regeneration. We have mainly introduced these following aspects: advantages and progress of chitosan hydrogels in vascular regeneration hydrogels and the modification of chitosan hydrogels to improve the application in vascular regeneration. Finally, this paper discusses the prospects of chitosan hydrogels for vascular regeneration. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although prefabricated flap is an ideal method to repair composite defects, the risk of flap necrosis is still an urgent problem to be solved. Therefore, promoting the revascularization of prefabricated flap can improve its survival rate and reduce complications. OBJECTIVE: To investigate the effect of expanded polytetrafluoroethylene membrane barrier material on vascular regeneration of prefabricated flap in rats. METHODS: Thirty SD rats were randomly divided into three groups with 10 rats in each group: control group, silica gel membrane group and expanded polytetrafluoroethylene group. In the silica gel membrane group and expanded polytetrafluoroethylene group, bilateral back arbitrary flaps (7.5 cm long and 1.5 cm wide) were prefabricated by the barrier delay method. Silica gel membrane and expanded polytetrafluoroethylene membrane were implanted under the flap. In the control group, the flap was prefabricated with non-barrier delay method, and the flap was directly sutured in situ without barrier under the flap. The vascular regeneration was observed after operation. At 14 days after operation, the flap tissue was stained with hematoxylin and eosin. Immunohistochemistry for vascular endothelial growth factor and CD34 was utilized to detect the activity of superoxide dismutase and the level of malondialdehyde. RESULTS AND CONCLUSION: (1) At 2 weeks after operation, the flap was cut again. In the silica gel membrane group, some rats had axial vascular regeneration and one rat had silicone curl. All rats in the expanded polytetrafluoroethylene group had obvious axial vessels. (2) The microvessel density of expanded polytetrafluoroethylene group was significantly higher than that of control group and silica gel membrane group (P < 0.05). The number of CD34 positive vessels in expanded polytetrafluoroethylene group was significantly higher than that in the control and silica gel membrane groups (P < 0.05). The integral absorbance of vascular endothelial growth factor protein in the expanded polytetrafluoroethylene group was significantly higher than that in the control and silica gel membrane groups (P < 0.05). (3) The activity of superoxide dismutase in the expanded polytetrafluoroethylene group was higher than that in the silica gel membrane group and control group (P < 0.05), and the level of malondialdehyde was lower than that in silica gel membrane group and control group (P < 0.05). (4) Using expanded polytetrafluoroethylene membrane as barrier delay material can promote the angiogenesis of prefabricated flap in rats, reduce oxidative stress, and improve the survival rate of the flap. [ABSTRACT FROM AUTHOR]

Extensive efforts have been made to achieve vascular regeneration accompanying tissue repair for treating vascular dysfunction-associated diseases. Recent advancements in stem cell biology and cell reprogramming have opened unforeseen opportunities to promote angiogenesis in vivo and generate autologous endothelial cells (ECs) for clinical use. We have, for the first time, identified a unique endothelial-specific transcription factor, ETV2/ER71, and revealed its essential role in regulating endothelial cell generation and function, along with vascular regeneration and tissue repair. Furthermore, we and other groups have demonstrated its ability to directly reprogram terminally differentiated non-ECs into functional ECs, proposing ETV2/ER71 as an effective therapeutic target for vascular diseases. In this review, we discuss the up-to-date status of studies on ETV2/ER71, spanning from its molecular mechanism to vasculo-angiogenic role and direct cell reprogramming toward ECs. Furthermore, we discuss future directions to deploy the clinical potential of ETV2/ER71 as a novel and potent target for vascular disorders such as cardiovascular disease, neurovascular impairment and cancer. [ABSTRACT FROM AUTHOR]

Organic erectile dysfunction (ED) is a type of sexual disorder in men that is usually associated with illness, surgical injury, normal aging and has a high incidence across the globe. And the essence of penile erection is a neurovascular event regulated by a combination of factors. Nerve and vascular injury are the main causes of erectile dysfunction. Currently, the main treatment options for ED include phosphodiesterase type 5 inhibitors (PDE5Is), intracorporeal injections and vacuum erection devices (VEDs), which are ineffective. Therefore, it is essential to find an emerging, non-invasive and effective treatment for ED. The histopathological damage causing ED can be improved or even reversed with hydrogels, in contrast to current therapies. Hydrogels have many advantages, they can be synthesized from various raw materials with different properties, possess a definite composition, and have good biocompatibility and biodegradability. These advantages make hydrogels an effective drug carrier. In this review, we began with an overview of the underlying mechanisms of organic erectile dysfunction, discussed the dilemmas of existing treatments for ED, and described the unique advantages of hydrogel over other approaches. Then emphasizing the progress of research on hydrogels in the treatment of ED.

Aim Myocardial infarction remains the leading cause of heart failure. The adult human heart lacks the capacity to undergo endogenous regeneration. New blood vessel growth is integral to regenerative medicine necessitating a comprehensive understanding of the pathways that regulate vascular regeneration. We sought to define the transcriptomic dynamics of coronary endothelial cells following ischaemic injuries in the developing and adult mouse and human heart and to identify new mechanistic insights and targets for cardiovascular regeneration. Methods and results We carried out a comprehensive meta-analysis of integrated single-cell RNA-sequencing data of coronary vascular endothelial cells from the developing and adult mouse and human heart spanning healthy and acute and chronic ischaemic cardiac disease. We identified species-conserved gene regulatory pathways aligned to endogenous neovascularization. We annotated injury-associated temporal shifts of the endothelial transcriptome and validated four genes: VEGF-C, KLF4, EGR1, and ZFP36. Moreover, we showed that ZFP36 regulates human coronary endothelial cell proliferation and defined that VEGF-C administration in vivo enhances clonal expansion of the cardiac vasculature post-myocardial infarction. Finally, we constructed a coronary endothelial cell meta-atlas, CrescENDO, to empower future in-depth research to target pathways associated with coronary neovascularization. Conclusion We present a high-resolution single-cell meta-atlas of healthy and injured coronary endothelial cells in the mouse and human heart, revealing a suite of novel targets with great potential to promote vascular regeneration, and providing a rich resource for therapeutic development. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is a globally prevalent disease with far-reaching medical and socio-economic consequences. Although improvements in treatment pathways and revascularisation therapies have slowed disease progression, contemporary management fails to modulate the underlying atherosclerotic process and sustainably replace damaged arterial tissue. Direct cellular reprogramming is a rapidly evolving and innovative tissue regenerative approach that holds promise to restore functional vasculature and restore blood perfusion. The approach utilises cell plasticity to directly convert somatic cells to another cell fate without a pluripotent stage. In this narrative literature review, we comprehensively analyse and compare direct reprogramming protocols to generate endothelial cells, vascular smooth muscle cells and vascular progenitors. Specifically, we carefully examine the reprogramming factors, their molecular mechanisms, conversion efficacies and therapeutic benefits for each induced vascular cell. Attention is given to the application of these novel approaches with tissue engineered vascular grafts as a therapeutic and disease-modelling platform for cardiovascular diseases. We conclude with a discussion on the ethics of direct reprogramming, its current challenges, and future perspectives. [ABSTRACT FROM AUTHOR]

The development of a biodegradable vascular scaffold (BVS) for the treatment of cardiovascular diseases (CVDs) still requires some improvement. Among them, re-endothelialization and anti-inflammation are clinically important to restore vascular function. In this study, we proposed a coating system to deliver hydrophilic bioactive agents to BVS using nanoemulsion and drop-casting methods. The poly(L-lactide) (PLLA) scaffold containing magnesium hydroxide (MH) was coated on the surface with bioactive molecules such as polydeoxyribonucleotide (PDRN), L-arginine (Arg, R), and mesenchymal stem cell-derived extracellular vesicles (EVs). PDRN upregulates the expression of VEGF as one of the A2A receptor agonists; and Arg, synthesized into nitric oxide by intracellular eNOS, induces endothelialization. In particular, EVs, which are composed of a lipid bilayer and transfer bioactive materials such as protein and nucleic acid, regulate homeostasis in blood vessels. Such a bioactive agent coating system and its PLLA composite suggest a new platform for the treatment of cardiovascular dysfunction. [ABSTRACT FROM AUTHOR]

Implementation of small-diameter tissue-engineered vascular grafts (TEVGs) into clinical practice is still delayed due to the frequent complications, including thrombosis, aneurysms, neointimal hyperplasia, calcification, atherosclerosis, and infection. Here, we conjugated a vasodilator/platelet inhibitor, iloprost, and an antimicrobial cationic amphiphilic drug, 1,5-bis-(4-tetradecyl-1,4-diazoniabicyclo [2.2.2]octan-1-yl) pentane tetrabromide, to the luminal surface of electrospun poly(ε-caprolactone) (PCL) TEVGs for preventing thrombosis and infection, additionally enveloped such TEVGs into the PCL sheath to preclude aneurysms, and implanted PCLIlo/CAD TEVGs into the ovine carotid artery (n = 12) for 6 months. The primary patency was 50% (6/12 animals). TEVGs were completely replaced with the vascular tissue, free from aneurysms, calcification, atherosclerosis and infection, completely endothelialised, and had clearly distinguishable medial and adventitial layers. Comparative proteomic profiling of TEVGs and contralateral carotid arteries found that TEVGs lacked contractile vascular smooth muscle cell markers, basement membrane components, and proteins mediating antioxidant defense, concurrently showing the protein signatures of upregulated protein synthesis, folding and assembly, enhanced energy metabolism, and macrophage-driven inflammation. Collectively, these results suggested a synchronised replacement of PCL with a newly formed vascular tissue but insufficient compliance of PCLIlo/CAD TEVGs, demanding their testing in the muscular artery position or stimulation of vascular smooth muscle cell specification after the implantation. [ABSTRACT FROM AUTHOR]

The advent of 4-dimensional (4D) light-sheet fluorescence microscopy (LSFM) has provided an entry point for rapid image acquisition to uncover real-time cardiovascular structure and function with high axial resolution and minimal photo-bleaching/-toxicity. We hereby review the fundamental principles of our LSFM system to investigate cardiovascular morphogenesis and regeneration after injury. LSFM enables us to reveal the micro-circulation of blood cells in the zebrafish embryo and assess cardiac ventricular remodeling in response to chemotherapy-induced injury using an automated segmentation approach. Next, we review two distinct mechanisms underlying zebrafish vascular regeneration following tail amputation. We elucidate the role of endothelial Notch signaling to restore vascular regeneration after exposure to the redox active ultrafine particles (UFP) in air pollutants. By manipulating the blood viscosity and subsequently, endothelial wall shear stress, we demonstrate the mechanism whereby hemodynamic shear forces impart both mechanical and metabolic effects to modulate vascular regeneration. Overall, the implementation of 4D LSFM allows for the elucidation of mechanisms governing cardiovascular injury and regeneration with high spatiotemporal resolution.

Aims Coronary vasculature formation is a critical event during cardiac development, essential for heart function throughout perinatal and adult life. However, current understanding of coronary vascular development has largely been derived from transgenic mouse models. The aim of this study was to characterize the transcriptome of the human foetal cardiac endothelium using single-cell RNA sequencing (scRNA-seq) to provide critical new insights into the cellular heterogeneity and transcriptional dynamics that underpin endothelial specification within the vasculature of the developing heart. Methods and results We acquired scRNA-seq data of over 10 000 foetal cardiac endothelial cells (ECs), revealing divergent EC subtypes including endocardial, capillary, venous, arterial, and lymphatic populations. Gene regulatory network analyses predicted roles for SMAD1 and MECOM in determining the identity of capillary and arterial populations, respectively. Trajectory inference analysis suggested an endocardial contribution to the coronary vasculature and subsequent arterialization of capillary endothelium accompanied by increasing MECOM expression. Comparative analysis of equivalent data from murine cardiac development demonstrated that transcriptional signatures defining endothelial subpopulations are largely conserved between human and mouse. Comprehensive characterization of the transcriptional response to MECOM knockdown in human embryonic stem cell-derived EC (hESC-EC) demonstrated an increase in the expression of non-arterial markers, including those enriched in venous EC. Conclusions scRNA-seq of the human foetal cardiac endothelium identified distinct EC populations. A predicted endocardial contribution to the developing coronary vasculature was identified, as well as subsequent arterial specification of capillary EC. Loss of MECOM in hESC-EC increased expression of non-arterial markers, suggesting a role in maintaining arterial EC identity. [ABSTRACT FROM AUTHOR]

As a result of thrombosis or intimal hyperplasia, synthetic artificial vascular grafts had a low success rate when they were used to replace small-diameter arteries (inner diameter < 6 mm). C-type natriuretic peptides (CNP) have anti-thrombotic effects, and can promote endothelial cell (EC) proliferation and inhibit vascular smooth muscle cell (SMC) over-growth. In this study, poly(ε-caprolactone) (PCL) vascular grafts loaded with CNP (PCL-CNP) were constructed by electrospinning. The PCL-CNP grafts were able to continuously release CNP at least 25 days in vitro. The results of scanning electron microscopy (SEM) and mechanical testing showed that the loading of CNP did not change the microstructure and mechanical properties of the PCL grafts. In vitro blood compatibility analysis displayed that PCL-CNP grafts could inhibit thrombin activity and reduce platelet adhesion and activation. In vitro cell experiments demonstrated that PCL-CNP grafts activated ERK1/2 and Akt signaling in human umbilical vein endothelial cells (HUVECs), as well as increased cyclin D1 expression, enhanced proliferation and migration, and increased vascular endothelial growth factor (VEGF) secretion and nitric oxide (NO) production. The rabbit arteriovenous (AV)-shunt ex vitro indicated that CNP loading significantly improved the antithrombogenicity of PCL grafts. The assessment of vascular grafts in rat abdominal aorta implantation model displayed that PCL-CNP grafts promoted the regeneration of ECs and contractile SMCs, modulated macrophage polarization toward M2 phenotype, and enhanced extracellular matrix remodeling. These findings confirmed for the first time that loading CNP is an effective approach to improve the hemocompatibility and vascular regeneration of synthetic vascular grafts. Small-diameter (< 6 mm) vascular grafts (SDVGs) have not been made clinically available due to their prevalence of thrombosis, limited endothelial regeneration and intimal hyperplasia. The incorporation of bioactive molecules into SDVGs serves as an effective solution to improve hemocompatibility and endothelialization. In this study, for the first time, we loaded C-type natriuretic peptides (CNP) into PCL grafts by electrospunning and confirmed the effectiveness of loading CNP on improving the hemocompatibility and vascular regeneration of artificial vascular grafts. Regenerative advantages included enhancement of endothelialization, modulation of macrophage polarization toward M2 phenotypes, and improved contractile smooth muscle cell regeneration. Our investigation brings attention to CNP as a valuable bioactive molecule for modifying cardiovascular biomaterial. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Exosomes produced by mesenchymal stem cells (MSCs) have vascular generative properties and are considered new effective candidates for the treatment of bone defects as alternatives to cell therapy. Improving the pro-regenerative function and efficacy of exosomes has been a popular research topic in the field of orthopaedics., Methods: We prepared mesoporous bioactive glass (mBG) microspheres via the template method. The ionic products of mBGs used to treat MSCs were extracted, and the effects of exosomes secreted by MSCs on osteoblast (OB) and macrophage (MP) behaviour and bone defect repair were observed in vivo (Micro-CT, H&E, Masson, and immunofluorescence staining for BMP2, COL1, VEGF, CD31, CD163, and iNOS)., Results: The mBG spheres were successfully prepared, and the Exo-mBG were isolated and extracted. Compared with those in the blank and Exo-Con groups, the proliferation and osteogenic differentiation of OBs in the Exo-mBG group were significantly greater. For example, on Day 7, OPN gene expression in the Ctrl-Exo group was 3.97 and 2.83 times greater than that in the blank and Exo-mBG groups, respectively. In a cranial defect rat model, Exo-mBG promoted bone tissue healing and angiogenesis, increased M2 macrophage polarisation and inhibited M1 macrophage polarisation, as verified by micro-CT, H&E staining, Masson staining and immunofluorescence staining. These effects may be due to the combination of a higher silicon concentration and a higher calcium-to-phosphorus ratio in the mBG ionic products., Conclusion: This study provides insights for the application of exosomes in cell-free therapy and a new scientific basis and technical approach for the utilisation of MSC-derived exosomes in bone defect repair., The Translational Potential of This Article: Our study demonstrated that exosomes produced by mBG-stimulated MSCs have excellent in vitro and in vivo bone-enabling and immunomodulatory functions and provides insights into the use of exosomes in clinical cell-free therapies., Competing Interests: We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (© 2024 The Authors.)

The significance of collagen and vascular in skin augmentation have been recognized in recent years. However, current skin tissue fillers, e.g. hyaluronic acid (HA) or HA-based hydrogel, fail to meet the perfect augmentation requirements due to their inadequate long-term support effect and the lack of tissue-inducing activity. Herein, an injectable skin filler containing hyaluronic acid (HA) hydrogel and lithium calcium silicate (LCS, Li 2 Ca 4 Si 4 O 13 ) bioceramic microspheres was developed for skin tissue fillers, owing to the excellent biological function of silicate bioceramics. The HA-LCS fillers could be easily injected through a tiny standard medical needle (27 G) with force of less than 36 N, and showed good biocompatibility both in vitro and in vivo . Furthermore, the bioactive ions released from HA-LCS fillers significantly enhanced the expression of vascularization-related genes and collagen-related genes. Importantly, the HA-LCS fillers not only stimulated the regeneration of mature blood vessels, but also promoted collagen secretion in dermal skin and filling area. This study not only presented an injectable filler with enhanced regeneration of blood vessels and collagen, but also provided a new strategy for developing tissue-induced fillers based on bioactive components of silicate bioceramics., Competing Interests: Chengtie Wu is an editorial board member for Bioactive Materials and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests., (© 2024 The Authors.)

In the case of wounds with exposed bone, it is essential to provide not only scaffolds with sufficient mechanical strength for protection, but also environments that are conducive to the regeneration of tissues and blood vessels. Despite the excellent biocompatibility and biodegradability of collagen and chondroitin sulfate, they display poor mechanical strength and rapid degradation rates. In contrast to previous methodologies that augmented the mechanical properties of biomaterials through the incorporation of additional substances, this investigation exclusively enhanced the mechanical strength of collagen/chondroitin sulfate scaffolds by modulating collagen concentrations. Furthermore, platelet-rich plasma (PRP) was employed to establish optimal conditions for vascular and tissue regeneration at the wound site. High-concentration collagen/chondroitin sulfate (H C-S) scaffolds were synthesized using high-speed centrifugation and combined with PRP, and their effects on endothelial cell proliferation were assessed. A porcine model of bone-exposed wounds was developed to investigate the healing effects and mechanisms. The experimental results indicated that scaffolds with increased collagen concentration significantly enhanced both tensile and compressive moduli. The combination of H C-S scaffolds with PRP markedly promoted endothelial cell proliferation. In vivo experiments demonstrated that this combination significantly accelerated the healing of porcine bone-exposed wounds and promoted vascular regeneration. This represents a promising strategy for promoting tissue regeneration that is worthy of further exploration and clinical application., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Li, Ahmad, Yue, Wang and Wu.)

Cell therapies harnessing the pro-vascular regenerative capacities of mesenchymal stromal cell (MSC) populations, including human adipose-derived stromal cells (hASCs), have generated considerable interest as an emerging treatment strategy for peripheral arterial disease (PAD) and its progression to critical limb ischemia (CLI). There is evidence to support that polysaccharide hydrogels can enhance therapeutic efficacy when applied as minimally-invasive delivery systems to support MSC survival and retention within ischemic tissues. However, there has been limited research to date on the effects of hydrogel composition on the phenotype and function of encapsulated cell populations. Recognizing this knowledge gap, this study compared the pro-angiogenic function of hASCs encapsulated in distinct but similarly-modified natural polysaccharide hydrogels composed of methacrylated glycol chitosan (MGC) and methacrylated hyaluronic acid (MHA). Initial in vitro studies confirmed high viability (>85%) of the hASCs following encapsulation and culture in the MGC and MHA hydrogels over 14 days, with a decrease in the cell density observed over time. Moreover, higher levels of a variety of secreted pro-angiogenic and immunomodulatory factors were detected in conditioned media samples collected from the hASCs encapsulated in the MGC-based hydrogels compared to the MHA hydrogels. Subsequent testing focused on comparing hASC delivery within the MGC and MHA hydrogels to saline controls in a femoral artery ligation-induced CLI (FAL-CLI) model in athymic nu/nu mice over 28 days. For the in vivo studies, the hASCs were engineered to express tdTomato and firefly luciferase to quantitatively compare the efficacy of the two platforms in supporting the localized retention of viable hASCs through longitudinal cell tracking with bioluminescence imaging (BLI). Interestingly, hASC retention was significantly enhanced when the cells were delivered in the MHA hydrogels as compared to the MGC hydrogels or saline. However, laser Doppler perfusion imaging (LDPI) indicated that the restoration of hindlimb perfusion was similar between the treatment groups and controls. These findings were corroborated by endpoint immunofluorescence (IF) staining showing similar levels of CD31 + cells in the ligated limbs at 28 days in all groups. Overall, this study demonstrates that enhanced MSC retention may be insufficient to augment vascular regeneration, emphasizing the complexity of designing biomaterials platforms for MSC delivery for therapeutic angiogenesis. In addition, the data points to a potential challenge in approaches that seek to harness the paracrine functionality of MSCs, as strategies that increase the secretion of immunomodulatory factors that can aid in regeneration may also lead to more rapid MSC clearance in vivo., (© 2024 The Author(s). Journal of Biomedical Materials Research Part A published by Wiley Periodicals LLC.)

Vascular graft maturation is associated with blood flow characteristics, such as velocity, pressure, vorticity, and wall shear stress (WSS). Many studies examined these factors separately. We aimed to examine the remodeling of arterio-venous fistulas (AVFs) and loop-shaped venous interposition grafts, together with 3D flow simulation. Thirty male Wistar rats were randomly and equally divided into sham-operated, AVF, and loop-shaped venous graft (Loop) groups, using the femoral and superficial inferior epigastric vessels for anastomoses. Five weeks after surgery, the vessels were removed for histological evaluation, or plastic castings were made and scanned for 3D flow simulation. Remodeling of AVF and looped grafts was complete in 5 weeks. Histology showed heterogeneous morphology depending on the distribution of intraluminal pressure and WSS. In the Loop group, an asymmetrical WSS distribution coincided with the intima hyperplasia spots. The tunica media was enlarged only when both pressure and WSS were high. The 3D flow simulation correlated with the histological findings, identifying "hotspots" for intimal hyperplasia formation, suggesting a predictive value. These observations can be useful for microvascular research and for quality control in microsurgical training. [ABSTRACT FROM AUTHOR]

Chitosan hydrogels have a wide range of applications in tissue engineering scaffolds, mainly due to the advantages of their chemical and physical properties. This review focuses on the application of chitosan hydrogels in tissue engineering scaffolds for vascular regeneration. We have mainly introduced these following aspects: advantages and progress of chitosan hydrogels in vascular regeneration hydrogels and the modification of chitosan hydrogels to improve the application in vascular regeneration. Finally, this paper discusses the prospects of chitosan hydrogels for vascular regeneration.

Stem cell therapy may be a promising option for the treatment of vascular diseases. In recent years, significant progress has been made in stem cell research, especially in the mechanism of stem cell activation, homing and differentiation in vascular repair and reconstruction. Current research on stem cells focuses on protein expression and transcriptional networks. Ion channels are considered to be the basis for the generation of bioelectrical signals, which control the proliferation, differentiation and migration of various cell types. Although heterogeneity of multiple ion channels has been found in different types of stem cells, it is unclear whether the heterogeneous expression of ion channels is related to different cell subpopulations and/or different stages of the cell cycle. There is still a long way to go in clinical treatment by using the regulation of stem cell ion channels. In this review, we reviewed the main ion channels found on stem cells, their expression and function in stem cell proliferation, differentiation and migration, and the research status of stem cells' involvement in vascular diseases. [Display omitted] • Ion channels play critical roles in regulating stem cell behaviors. • Heterogeneous expression of ion channels and functional significance requires further investigation. [ABSTRACT FROM AUTHOR]

In recent years, tissue engineering researchers have exploited a variety of biomaterials that can potentially mimic the extracellular matrix (ECM) for tissue regeneration. Natural cellulose, mainly obtained from bacterial (BC) and plant-based (PC) sources, can serve as a high-potential scaffold material for different regenerative purposes. Natural cellulose has drawn the attention of researchers due to its advantages over synthetic cellulose including its availability, cost effectiveness, perfusability, biocompatibility, negligible toxicity, mild immune response, and imitation of native tissues. In this article, we review recent in vivo and in vitro studies which aimed to assess the potential of natural cellulose for the purpose of soft (skin, heart, vein, nerve, etc.) and hard (bone and tooth) tissue engineering. Based on the current research progress report, it is sensible to conclude that this emerging field of study is yet to satisfy the clinical translation criteria, though reaching that level of application does not seem far-fetched. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mesenchymal stem cells have the functions of inhibiting inflammation and cell apoptosis, promoting tissue repair, angiogenesis, and immune regulation in ischemic heart disease. OBJECTIVE: To review the latest research progress of mesenchymal stem cells in myocardial ischemia-reperfusion injury to provide ideas and basis for their further research and clinical application. METHODS: PubMed, Wanfang, and CNKI databases were searched for relevant literature. The key words were “mesenchymal stem cell, MSCs, myocardial ischemia-reperfusion injury, MIRI, exosomes, inflammation, tissue repair, vascular regeneration” in Chinese and English, separately. Finally, 48 articles were included and further summarized. RESULTS AND CONCLUSION: Myocardial ischemia-reperfusion injury is a common pathophysiological process in clinical heart diseases. It is common in ischemic cardiomyopathy, cardiopulmonary bypass and heart transplantation. Its mechanisms include free radical damage, calcium ion overload, energy metabolism disorders, and inflammation and so on. In recent years, the treatment of mesenchymal stem cell transplantation has attracted attention. Its exosomal function, myocardial tissue repair, reduction of myocardial cell apoptosis and inhibition of inflammation provide a new idea for treatment of myocardial ischemiareperfusion injury. Adult mesenchymal stem cells are currently the first choice for the treatment of myocardial ischemia-reperfusion injury. Therefore, a better understanding of the mechanism of mesenchymal stem cells in myocardial ischemia-reperfusion injury and the latest research progress are extremely important for their in-depth research and clinical application. [ABSTRACT FROM AUTHOR]

The establishment of effective vascularization represents a key challenge in regenerative medicine. Adequate sources of vascular cells and intact vessel fragments have not yet been explored. We herein examined the potential application of microvessels induced from hiPSCs for rapid angiogenesis and tissue regeneration. Microvessels were generated from human pluripotent stem cells (iMVs) under a defined induction protocol and compared with human adipose tissue-derived microvessels (ad-MVs) to illustrate the similarity and differences of the alternative source. Then, the therapeutic effect of iMVs was detected by transplantation in vivo. The renal ischemia-reperfusion model and skin damage model were applied to explore the potential effect of vascular cells derived from iMVs (iMVs-VCs). Besides, the subcutaneous transplantation model and muscle injury model were established to explore the ability of iMVs for angiogenesis and tissue regeneration. The results revealed that iMVs had remarkable similarities to natural blood vessels in structure and cellular composition, and were potent for vascular formation and self-organization. The infusion of iMVs-VCs promoted tissue repair in the renal and skin damage model through direct contribution to the reconstruction of blood vessels and modulation of the immune microenvironment. Moreover, the transplantation of intact iMVs could form a massive perfused blood vessel and promote muscle regeneration at the early stage. The infusion of iMVs-VCs could facilitate the reconstruction and regeneration of blood vessels and modulation of the immune microenvironment to restore structures and functions of damaged tissues. Meanwhile, the intact iMVs could rapidly form perfused vessels and promote muscle regeneration. With the advantages of abundant sources and high angiogenesis potency, iMVs could be a candidate source for vascularization units for regenerative medicine. [ABSTRACT FROM AUTHOR]

The progression of cardiovascular diseases such as atherosclerosis and myocardial infarction leads to serious vascular injury, highlighting the urgent need for targeted regenerative therapy. Extracellular vesicles (EVs) composed of a lipid bilayer containing nuclear and cytosolic materials are relevant to the progression of cardiovascular diseases. Moreover, EVs can deliver bioactive cargo in pathological cardiovascular and regulate the biological function of recipient cells, such as inflammation, proliferation, angiogenesis and polarization. However, because the targeting and bioactivity of natural EVs are subject to several limitations, bioengineered EVs have achieved wide advancements in biomedicine. Bioengineered EVs involve three main ways to acquire including (i) modification of the EVs after isolation; (ii) modification of producer cells before EVs' isolation; (iii) synthesize EVs using natural or modified cell membranes, and encapsulating drugs or bioactive molecules into EVs. In this review, we first summarize the cardiovascular injury-related disease and describe the role of different cells and EVs in vascular regeneration. We also discuss the application of bioengineered EVs from different producer cells to cardiovascular diseases. Finally, we summarize the surface modification on EVs which can specifically target abnormal cells in injured vascular. [ABSTRACT FROM AUTHOR]

Abstract Background The permeability of the blood-spinal cord barrier (BSCB) is mainly determined by junction complexes between adjacent endothelial cells (ECs), including tight junctions (TJs) and adherens junctions (AJs), which can be severely damaged after spinal cord injury (SCI). Exercise training is a recognized method for the treatment of SCI. The destruction of the BSCB mediated by matrix metalloproteinases (MMPs) leads to inflammation, neurotoxin production, and neuronal apoptosis. The failure of new blood vessels to effectively regenerate is also an important cause of delayed recovery after SCI. For the first time, we introduced water treadmill training (TT) to help SCI rats successfully exercise and measured the effects of TT in promoting recovery after SCI and the possible mechanisms involved. Methods Sprague-Dawley (200–250 g) rats were randomly divided into the following three groups: sham operated, SCI, and SCI + TT. Animals were sacrificed at 7 or 14 days post-surgery. The degree of neurological deficit, tissue morphology and BSCB permeability were assessed by the Basso-Beattie-Bresnahan (BBB) motor function scale and appropriate staining protocols, and apoptosis, protein expression and vascular EC ultrastructure were assessed by TUNEL staining, Western blotting, immunofluorescence and transmission electron microscopy (TEM). Results Our experiments showed that TT reduced permeability of the BSCB and decreased structural tissue damage. TT significantly improved functional recovery when compared with that in the SCI group; TJ and AJ proteins expression increased significantly after TT, and training reduced apoptosis induced by SCI. TT could promote angiogenesis, and MMP-2 and MMP-9 expression was significantly inhibited by TT. Conclusions The results of this study indicate that TT promotes functional recovery for the following reasons: TT (1) protects residual BSCB structure from further damage, (2) promotes vascular regeneration, and (3) inhibits MMP-2/9 expression to mitigate BSCB damage.

Xuejing Yue,1 Lixia Liu,1 Haiqing Yan,2 Yongkun Gui,2 Jun Zhao,2 Ping Zhang2 1School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang 453003, Henan, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, People’s Republic of ChinaCorrespondence: Ping ZhangDepartment of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, People’s Republic of ChinaTel +86-373-3029917Email zhangpingsjnk@126.comBackground: IL-12 inhibition of the endothelial cell functions and angiogenesis is mediated by the cross-talk between the lymphocyte and the endothelial cells, which plays a key role in inhibiting the process of angiogenesis in the eyeballs and in malignant tumors.Methods: We established the intracerebral hemorrhage (ICH) rat model, and IL-12 receptor beta monoclonal antibody was injected into the ICH rats. Western blot, immunofluorescence and RT-qPCR were used to detect the gene expression. Brain water content, EB staining, Garcia test, Beam walking test and wire hanging test were used to assess the injury of brain in ICH rats.Results: IL-12 gene was significantly increase in hematoma border tissue of ICH rats, and IL-12 protein mainly localized in monocytes. Anti-IL-12 treatment with IL-12 monoclonal antibodies could not only significantly decrease the brain water content and EB content in brain tissues of ICH rats, but also significantly increase the score of the Garcia, Beam balance and the Wire hanging test in ICH rats. Moreover, anti-IL-12 treatment significantly decrease the expression of pro-inflammatory gene, inflammatory gene, p-JAK2/JAK2 and p-STAT4/STAT4 protein, but significantly increase the expression anti-inflammatory gene and CD31 protein, and M2 macrophage ratio in hematoma border tissues of ICH rats. In vitro, rmIL-12 inhibited the tube formation of brain microvascular endothelial cells (BMVES) in BMVES and bone marrow-derived monocytes (BMDM) co-culture systems, but not work in a separately cultured BMVES system. In addition, Fedratinib not only reduced p-JAK2/JAK2 and p-STAT4/STAT4 protein expression in BMDM after treating with b-FGF and rmIL-12, but also significantly increased the tube formation of BMVES in BMVES and BMDM co-culture systems after treating with b-FGF and rmIL-12.Conclusion: Blockade of IL-12 receptor attenuated brain injury after ICH in rat by promoting angiogenesis, and the mechanism might be related to blocking IL-12 could inhibit M2 cell activation via the JAK2/STAT4 pathway.Keywords: interleukin-12, intracerebral hemorrhage, vascular regeneration, macrophages