Expression Of Angiogenic Factors Research Articles

Cancer-associated Fibroblasts-derived Exosomes with HOXD11 Overexpression Promote Ovarian Cancer Cell Angiogenesis Via FN1.

Cancer-associated fibroblasts (CAFs) represent a critical stromal component of metastatic niche and promote metastasis in patients with ovarian cancer (OC). Here, we try to further understand the mechanism by which CAFs-derived exosomes (CAFs-Exo) promoted angiogenesis in OC. We intersected differentially expressed genes in OC cells after CAFs-Exo treatment in the GSE147610 dataset with a list of transcription factors to identify homeobox protein hox-D11 (HOXD11) as a possible cargo of CAFs-Exo. HOXD11 encapsulated by CAFs-Exo enhanced colony formation, migration, and invasion of OC cells. HOXD11 bound to the promoter of fibronectin (FN1) and promoted its transcription. HOXD11 knockdown from CAFs-Exo significantly repressed the VEGF and CD31 protein expression and tube formation, viability, and migration of human umbilical vein endothelial cells (HUVEC) and slowed angiogenesis and tumor growth in mice. Furthermore, we found that overexpression of FN1 increased the expression of angiogenic factors and activity of HUVEC in the presence of HOXD11 knockdown. These results verify the significant contribution of CAFs-Exo to angiogenesis in OC, which could be partially due to the promotion of FN1 mediated by HOXD11.

Potential of Sulodexide in the Treatment of Diabetic Retinopathy and Retinal Vein Occlusion.

Retinal vascular diseases, such as diabetic retinopathy or retinal vein occlusion, are common causes of severe vision loss. Central to the pathophysiology of these conditions are endothelial dysfunction, inflammation, capillary leakage, ischemia, and pathological neoangiogenesis. Capillary damage leads to leakage and the development of macular edema, which is associated with vision loss and requires complex treatment. Sulodexide, a glycosaminoglycan composed of heparan sulfate and dermatan sulfate with high oral bioavailability, exhibits several favorable pharmacologic properties, including antithrombotic, anti-inflammatory, and endothelium-protective effects. Additionally, treatment with sulodexide has been associated with the reduction of oxidative stress and decreased expression of angiogenic growth factors, such as vascular endothelial growth factor. This review aims to provide an overview of the pharmacological properties, mechanisms of action, and therapeutic effects of sulodexide. Furthermore, its potential for clinical application in venous and diabetic diseases, such as venous thromboembolism, chronic venous insufficiency, peripheral artery disease, or diabetic nephropathy, is summarized. We also present experimental and clinical studies evaluating the potential of sulodexide in ocular conditions and discuss its therapeutic implications for the treatment of retinal vascular diseases.

Biodegradable oxygen-evolving metalloantibiotics for spatiotemporal sono-metalloimmunotherapy against orthopaedic biofilm infections

Pathogen-host competition for manganese and intricate immunostimulatory pathways severely attenuates the efficacy of antibacterial immunotherapy against biofilm infections associated with orthopaedic implants. Herein, we introduce a spatiotemporal sono-metalloimmunotherapy (SMIT) strategy aimed at efficient biofilm ablation by custom design of ingenious biomimetic metal-organic framework (PCN-224)-coated MnO2-hydrangea nanoparticles (MnPM) as a metalloantibiotic. Upon reaching the acidic H2O2-enriched biofilm microenvironment, MnPM can convert abundant H2O2 into oxygen, which is conducive to significantly enhancing the efficacy of ultrasound (US)-triggered sonodynamic therapy (SDT), thereby exposing bacteria-associated antigens (BAAs). Moreover, MnPM disrupts bacterial homeostasis, further killing more bacteria. Then, the Mn ions released from the degraded MnO2 can recharge immune cells to enhance the cGAS-STING signaling pathway sensing of BAAs, further boosting the immune response and suppressing biofilm growth via biofilm-specific T cell responses. Following US withdrawal, the sustained oxygenation promotes the survival and migration of fibroblasts, stimulates the expression of angiogenic growth factors and angiogenesis, and neutralizes excessive inflammation. Our findings highlight that MnPM may act as an immune costimulatory metalloantibiotic to regulate the cGAS-STING signaling pathway, presenting a promising alternative to antibiotics for orthopaedic biofilm infection treatment and pro-tissue repair.

Ultrasound based radiomics model for assessment of placental function in pregnancies with preeclampsia

The goal of our research is to elucidate and better assess placental function in rats with preeclampsia through an innovative application of ultrasound-based radiomics. Using a rat model induced with L-NAME, we carefully investigated placental dysfunction via microstructural analysis and immunoprotein level assessment. Employing the Boruta feature selection method on ultrasound images facilitated the identification of crucial features, consequently enabling the development of a robust model for classifying placental dysfunction. Our study included 12 pregnant rats, and thorough placental evaluations were conducted on 160 fetal rats. Distinct alterations in placental microstructure and angiogenic factor expression were evident in rats with preeclampsia. Leveraging high-throughput mining of quantitative image features, we extracted 558 radiomic features, which were subsequently used to construct an impressive evaluation model with an area under the receiver operating curve (AUC) of 0.95. This model also exhibited a remarkable sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 88.7%, 91.5%, 90.2%, 90.4%, and 90.0%, respectively. Our findings highlight the ability of ultrasound-based radiomics to detect abnormal placental features, demonstrating its potential for evaluating both normative and impaired placental function with high precision and reliability.

Human cranial bone-derived mesenchymal stem cells cultured under simulated microgravity can improve cerebral infarction in rats

The efficacy of transplanting human cranial bone-derived mesenchymal stem cells (hcMSCs) cultured under simulated microgravity (sMG) conditions has been previously reported; however, their effect on cerebral infarction remains unknown. Here, we examined the efficacy of transplanting hcMSCs cultured in an sMG environment into rat models of cerebral infarction. For evaluating neurological function, hcMSCs cultured in either a normal gravity (1G) or an sMG environment were transplanted in rats 1 day after inducing cerebral infarction. The expression of endogenous neurotrophic, axonal, neuronal, synaptogenic, angiogenic, and apoptosis-related factors in infarcted rat brain tissue was examined using real-time polymerase chain reaction and western blotting 35 days after stroke induction. The RNAs of hcMSCs cultured under 1G or sMG environments were sequenced. The results showed that neurological function was significantly improved after transplantation of hcMSCs from the sMG group compared with that from the 1G group. mRNA expressions of nerve growth factor, fibroblast growth factor 2, and synaptophysin were significantly higher in the sMG group than in the 1G group, whereas sortilin 1 expression was significantly lower. RNA sequencing analysis revealed that genes related to cell proliferation, angiogenesis, neurotrophy, neural and synaptic organization, and inhibition of cell differentiation were significantly upregulated in the sMG group. In contrast, genes promoting microtubule and extracellular matrix formation and cell adhesion, signaling, and differentiation were downregulated. These results demonstrate that hcMSCs cultured in the sMG environment may be a useful source of stem cells for the recovery of neurological function after cerebral infarction.

Effect of Silica Nanoparticle Treatment on Adhesion between Tissue-like Substrates and In Vivo Skin Wound Sealing.

Silica nanoparticles are innovative solutions of surgical glue that can readily adhere to various tissue-like substrates without the need for time-consuming chemical reactions or ultraviolet irradiation. Herein, 10 nm-sized silica nanoparticle (SiNP10) treatment exhibited maximum adhesion strength in the porcine heart tissue model, which was approximately 7.15 times higher than that of the control group of non-treatment. We assessed the effects of silica nanoparticle treatment on in vivo skin wounds by scoring tissue adhesion and inflammation using histological images. Compared to the commercial cyanoacrylate skin adhesive (Dermabond), suppression of inflammatory cytokine levels in the incision wound skin was observed. We further quantified the expression of angiogenic growth factors and connective tissue formation-related proteins. On day 5 after wound closing treatment, the expression levels of PDGF-BB growth factor were significantly higher in SiNP10 treatment (0.64 ± 0.03) compared to Dermabond (0.07 ± 0.05). This stimulated angiogenesis and connective tissue formation in the skin of the incision wound may be associated with the promoting effects of SiNP10 treatment on wound closure and tissue adhesion.

Predictive potential of dynamic contrast-enhanced MRI and plasma-derived angiogenic factors for response to concurrent chemoradiotherapy in human papillomavirus-negative oropharyngeal cancer.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascularity, which depends on the process of angiogenesis and affects tumour response to treatment. Our study explored the associations between DCE-MRI parameters and the expression of plasma angiogenic factors in human papilloma virus (HPV)-negative oropharyngeal cancer, as well as their predictive value for response to concurrent chemoradiotherapy (cCRT). Twenty-five patients with locally advanced HPV-negative oropharyngeal carcinoma were prospectively enrolled in the study. DCE-MRI and blood plasma sampling were conducted before cCRT, after receiving a radiation dose of 20 Gy, and after the completion of cCRT. Perfusion parameters ktrans, kep, Ve, initial area under the curve (iAUC) and plasma expression levels of angiogenic factors (vascular endothelial growth factor [VEGF], connective tissue growth factor [CTGF], platelet-derived growth factor [PDGF]-AB, angiogenin [ANG], endostatin [END] and thrombospondin-1 [THBS1]) were measured at each time-point. Patients were stratified into responders and non-responders based on clinical evaluation. Differences and correlations between measures were used to generate prognostic models for response prediction. Higher perfusion parameter ktrans and higher plasma VEGF levels successfully discriminated responders from non-responders across all measured time-points, whereas higher iAUC and higher plasma PDGF-AB levels were also discriminative at selected time points. Using early intra-treatment measurements of ktrans and VEGF, a predictive model was created with cut-off values of 0.259 min-1 for ktrans and 62.5 pg/mL for plasma VEGF. Early intra-treatment DCE-MRI parameter ktrans and plasma VEGF levels may be valuable early predictors of response to cCRT in HPV-negative oropharyngeal cancer.

Directing Rat Hair Follicle Stem Cells Toward Neuronal Lineage With Enhanced Trophic Factor Expression.

Hair follicle stem cells (HFSCs) are promising candidates for cell-based therapies in neurodegenerative diseases because of their ability to differentiate into neural lineages and exert paracrine effects in damaged tissues. However, their clinical application faces challenges, particularly in efficiently guiding them toward neural lineages. This study explores using chick embryo extract (CEE) to enhance HFSCs' secretory capacity and neuronal differentiation. HFSCs from rat whisker pads were cultured in growth medium supplemented with either 20% FBS or a combination of 10% FBS and 10% CEE, transitioning to 20% FBS after the first subculture. We conducted gene expression profiling of lineage commitment markers and neurotrophic factors in both experimental groups, alongside morphological assessments and protein expression analyses. CEE supplementation during migration increased neuronal differentiation, evidenced by more cells with neurites and higher MAP2 expression at both the gene and protein levels. CEE also inhibited the expression of PDGFR-α, indicating a suppression of differentiation toward Schwann cells. Furthermore, we observed increased levels of trophic factors such as BDNF and VEGF at passage 3 induced by CEE supplementation. Enhancing the neuronal lineage commitment of hair follicle stem cells (HFSCs) and boosting the expression of trophic and angiogenic factors through short-term CEE preconditioning during their migratory stage presents a compelling approach. This strategy holds great promise in enhancing the effectiveness of stem cell-based therapies for neurological disorders.

P215 EFFECT OF OXYGEN LOADING MODEL ON RETINOPATHY OF PREMATURITY IN INTRAUTERINE GROWTH RETARDED MICE

Background and Objective: Fetal growth retardation (IUGR) not only induces various complications in newborns, but is also known to be associated with the future development of lifestyle-related diseases and conditions. Therefore, the neonatal treatment often struggles between life-sustaining and oxygen administration. We have previously reported that IUGR mice born from mothers raised on a low-protein diet show enhanced vascular remodeling. The mechanism is influenced by an increased inflammatory response associated with a decreased angiogenic response due to hypoxic loading in a femoral artery cuff implantation model. Based on this, we hypothesized that in IUGR mice, the reduced angiogenic response in retinopathy of prematurity may work to suppress the onset of the disease. To test this hypothesis, we examined the effects of oxygen loading on the retinal neovasculature using the mouse oxygen-induced retinopathy of prematurity (OIR) model. Methods The OIR model was created in newborns born from mothers raised on a normal protein diet (20%) and in IUGR newborns born from mothers raised on a low protein diet (8%). Specifically, the newborns were exposed to 75% hyperoxia for 5 days starting at 7 days of age, and retinal neovascularization was histologically evaluated 5 days later at 17 days of age for comprehensive transcriptome analysis. Results: Compared to normal birth weight OIR mice, retinal neovascularization was significantly suppressed in OIR mice with FGR. Retinal RNA sequencing revealed decreased expression of angiogenic factors that trigger pathological retinal neovascularization, such as the mitogen-activated protein kinase pathway (MAPK) pathway and corresponding upstream signaling pathways. Conclusions Our findings suggest that IUGR neonates have a weaker response to retinal oxygen stress and consequently are likely to have reduced retinopathy of prematurity. These results indicate that the risk of developing retinopathy of prematurity is attenuated in IUGR neonates compared to mature neonates with normal birth weight.

O96 NICD LACTYLATION OF NOTCH SIGNALING IMPROVES MICROVASCULATION RAREFACTION IN HYPERTENSION

Background and Objective: Microvascular rarefaction is a key pathophysiologic basis of hypertension-related cardiovascular disease. Exercise decreases blood pressure and promotes angiogenesis related to inhibition of NOTCH signaling. The activation of the NOTCH pathway depends on the transcriptional regulation of its intracellular active fragment NICD after nuclear translocation. The post-translational modification status of proteins plays a crucial role in the nuclear translocation effect of transcription factors. Lactylation is influenced by the level of lactate in the body. Exercise can promote glycolysis in endothelial cells, and increase intracellular lactate levels. Therefore, we explored whether the beneficial effects of Exercise were mediated by promoting NICD lactylation, inhibiting the NOTCH signaling, and promoting angiogenesis. Methods: To test our hypotheses, WKYs (normotensive rats) and SHRs (spontaneously hypertensive rats) were given exercise for 12 weeks. Blood pressure was determined by the tail-cuff method, and cardiac function was assessed by echocardiography. Using rats’ retina, gastrocnemius, and myocardium detected microvascular density. The expression levels of NOTCH signaling pathway related proteins and angiogenesis related factors were measured by Western Blotting. The level of lactate was measured by using a lactate assay kit. Protein modification omics was used to detect the modification types and levels of NICD in microvascular endothelial cells, followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to detect the lactylation sites of NICD in microvascular endothelial cells. Results: Exercise in SHRs resulted in reduced blood pressure and concentric hypertrophy. Exercise promoted angiogenesis and improved microcirculation rarefaction. Exercise also reduced the production of NOTCH pathway related proteins and increased the expression level of angiogenesis related factors. The lactate level increased after exercise, and the lactylation level of NICD increased. Conclusions: In summary, Exercise decreases hypertension and improves cardiac function in SHRs. Our research results indicated that exercise increases lactate production and induces NICD lactylation, thereby inhibiting the NOTCH signaling, upregulating the expression of angiogenic factors, promoting angiogenesis, and lowering blood pressure.

Exogenous melatonin ameliorates embryo-maternal cross-talk in early pregnancy in sheep.

Melatonin plays a crucial role in enhancing reproductive performance in small ruminants. This paper reveals the effects of exogenous melatonin on the placental and endometrial rearrangement in early pregnancy in sheep. Early pregnancy losses cause 25% of pregnancy failures in small ruminants because of asynchrony between conceptus and uterine signals. In this context, melatonin plays a crucial role in sheep reproductive dynamics, but little is known about its effects during the peri-implantation period. We hypothesized that melatonin supports embryo implantation by modulating the uterine microenvironment. This study aimed to assess the effects of exogenous melatonin on the endometrial and early placental rearrangement. Ten multiparous ewes either did (MEL, n = 5) or did not (CTR, n = 5) receive a subcutaneous melatonin implant (18 mg) 50 days before a synchronized mating. On day 21 of pregnancy, the sheep were euthanized. MEL ewes exhibited a higher prolificity rate (2.8 vs 2.0 embryos/ewe) and plasma progesterone levels (3.84 vs 2.96 ng/mL, P < 0.05) than did CTR ewes. Groups did not differ significantly in embryo crown-rump length. MEL placentas had significantly (P < 0.001) more binucleated trophoblast cells in the chorion region, and ovine placental lactogen expression was significantly (P < 0.05) more strongly upregulated than in CTR. Exogenous melatonin increased significantly (P < 0.05) gene expression of angiogenic factors (VEGFA, VEGFR1, IGF1R), IFNAR2, and PR in the caruncular endometrium. Expression of the MT2 receptor in the endometrium and placenta was significantly (P < 0.05) higher in the MEL group. These results indicate that melatonin implants acted differentially on uterine and placental rearrangement. Melatonin increases differentiation in the placenta and induces changes that could promote vessel maturation in the endometrium, suggesting that it enhances the uterine microenvironment in the early stage of pregnancy in sheep.

The Pivotal Role of the Key Angiogenic Factors in the Development of Endometrioid Pathologies of the Uterus and Ovary.

A characteristic feature of uterine pathologies is a specific change in cell metabolism, which predominantly manifests as a shift in the need for nutrients, thereby directing cells to engage in different angiogenic marker activities. Angiogenesis is one of the main signals supporting the survival and development of cells and tissues not only under physiological conditions. Therefore, it is necessary that we understand pathological hyperactivation in all uterine diseases, from endometriosis through ovarian endometrioid adenocarcinoma to malignant transformed cells of the uterine epithelium and body. This work presents the gene expression results of selected angiogenesis targets (VEGF-A, TGF-β1, ANG1/2, and HIF-1α), cell migration, and cell-cell interaction determined in vitro. Our results suggest that angiogenesis varies in the tested pathological conditions (ectopic endometriosis-12Z; ovarian endometrioid adenocarcinoma-A2780; tumors-SK-UT-1 and RL-95-2) compared to physiological angiogenesis (HME1). The differential expression of angiogenic factors may contribute (or is a contributing factor) to the observed differences to acknowledge an inherent variability in angiogenesis among cell lines. Determining the genomic phenomena responsible for processes associated with inadequate angiogenesis in the pelvic region could help us to develop individual treatment strategies and explain resistance to treatment.

HIF-1α–dependent regulation of angiogenic factor expression in Müller cells by mechanical stimulation

Mechanical stress regulates various biological processes in cells, tissues, and organs as well as contributes to the pathogenesis of various diseases. The retina is subjected to mechanical stress imposed by intraocular pressure as well as by retinal hemorrhage and edema. Responses to mechanical stress have been studied in retinal pigment epithelial cells and Müller cells of the retina, with the former cells having been found to undergo a stress-induced increase in the expression of vascular endothelial growth factor (VEGF), which plays a key role in physiological and pathological angiogenesis in the retina. We here examined the effects of stretch stimulation on the expression of angiogenic factors in cultured human Müller cells. Reverse transcription and quantitative PCR analysis revealed that expression of the VEGF-A gene was increased by such stimulation in Müller cells, whereas that of the angiopoietin 1 gene was decreased. An enzyme-linked immunosorbent assay showed that stretch stimulation also increased VEGF secretion from these cells. Expression of the transcription factor HIF-1α (hypoxia-inducible factor–1α) was increased at both mRNA and protein levels by stretch stimulation, and the HIF-1α inhibitor CAY10585 prevented the effects of mechanical stress on VEGF-A gene expression and VEGF secretion. Furthermore, RNA-sequencing analysis showed that the expression of angiogenesis-related pathway genes was upregulated by stretch stimulation. Our results thus suggest that mechanical stress induces VEGF production in Müller cells in a manner dependent on HIF-1α, and that HIF-1α is therefore a potential therapeutic target for conditions such as diabetic retinopathy, age-related macular degeneration, and retinal vein occlusion.

Exploring the Nexus of Steroidal Hormone Receptor, Uterine VEGF Expression and NADPH-d Interaction in Buffalo Uterus During Oestrous Cycle With Seasonal Variation.

The reproductive efficiency in buffalo is highly influenced by seasonal variability. Angiogenesis in the reproductive cycle is important for optimal physiological functioning of uterus. Estrogen receptor-α (ERα), vascular endothelial growth factor (VEGF) and reduced nicotinamide adenine dinucleotide phosphatase diaphorase (NADPH-d) are vital indicators for the uterine angiogenic process. This study was conducted to see the effect of season on the expression of different uterine angiogenic factors. Season wise (winter and summer) and phase wise (follicular and luteal), immune staining intensity of buffalo uterus was measured by calculating the optical density value (OD) for ERα and VEGF. Percentage of immuno-positive cell count for ERα was done. Histoenzymic NADPH-d expression was analysed. Expression of all these factors increased during follicular phase of oestrous cycle in order to support the angiogenesis; however, the expression was significantly lower (p ≤ 0.05) in term of OD value as well as percentage count of immuno-positive cells during summer season indicating lower angiogenic activity that subsequently affected reproduction in buffalo.

Ginsenoside Rg1 regulates astrocytes to promote angiogenesis in spinal cord injury via the JAK2/STAT3 signaling pathway

Ethnopharmacological relevanceGinseng (Panax ginseng C. A. Mey) is a common traditional Chinese medicine used for anti-inflammation, anti-apoptosis, anti-oxidative stress, and neuroprotection. Ginsenosides Rg1, the main active components isolated from ginseng, may be a feasible therapy for spinal cord injury (SCI). Aims of the studySCI causes endothelial cell death and blood vessel rupture, ultimately resulting in long-term neurological impairment. As a result, encouraging spinal angiogenesis may be a feasible therapy for SCI. This investigation aimed to validate the capacity of ginsenoside Rg1 in stimulating angiogenesis within the spinal cord. Materials and methodsRats with SCI were injected intraperitoneally with ginsenoside Rg1. The effectiveness of ginsenoside Rg1 was assessed using the motor function score and the motor-evoked potential (MEP). Immunofluorescence techniques were applied to identify the spinal cord's angiogenesis. Angiogenic factors were examined through Western Blot (WB) and Immunohistochemistry. Oxygen-glucose deprivation (OGD) was employed to establish the hypoxia-ischemia model in vitro, and astrocytes (As) were given ginsenoside Rg1 and co-cultured with spinal cord microvascular endothelial cells (SCMECs). Immunofluorescence, wound healing test, and tube formation assay were used to identify the co-cultured SCMECs' activity. Finally, network pharmacology analysis and siRNA transfection were applied to verify the mechanism of ginsenoside Rg1 promoting angiogenesis. ResultsThe rats with SCI treated with ginsenoside Rg1 indicated more significant functional recovery, more pronounced angiogenesis, and higher levels of angiogenic factor expression. In vitro, the co-culture system with ginsenoside Rg1 intervention improved SCMECs' capacity for proliferating, migrating, and forming tubes, possibly by promoting the expression of vascular endothelial growth factor (VEGF) in As via the janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. ConclusionGinsenoside Rg1 can regulate As to promote angiogenesis, which may help to understand the mechanism of promoting SCI recovery.

A Fe2O3/CNx cascade nanoreactor with dual-enzyme-mimetic activities for cancer hypoxia relief to amplify chemo/photodynamic therapy

Reactive oxygen species (ROS)-mediated therapeutic strategies, including chemodynamic therapy (CDT), photodynamic therapy (PDT), and their combination, are effective for treating cancer. Developing a nanoreactor with combined functions of catalase (CAT) and peroxidase (POD) that can simultaneously convert excess H2O2 in tumors into O2 required for type II PDT and hydroxyl radicals (•OH) for CDT can help achieve combined therapy. Here, we reported on a safe Fe2O3/CNx nanoreactor with dual enzyme simulated activity, in which CNx sheet was the carrier and reducing agent to convert Fe2O3 to Fe2+. After modified by MgO2 and photosensitizer Ce6, MgO2-Fe2O3/CNx-Ce6 (MFCC) platform integrated multiple functions, including photosensitizer delivery, compensated H2O2 continuous supply, relieve of hypoxia, generation of •OH and consumption of GSH into a single formulation. Under 660 nm irradiation for 4 min, MFCC actives more ROS to conduct PDT/CDT, leading to the remarkable reduced survival rate of breast cancer cells to 14 %. Due to the enhanced permeability and retention (EPR) effect, MFCC can retain and accumulate at the tumor site of mice for a longer period that inhibit the expression of tumor angiogenic factors, suppress tumor neovascularization, and suppress the proliferation and growth of tumor cells.

Novel fabrication of macromolecular multi-functional hydrogel encapsulated with HUCB-derived mesenchymal stem cells to effective regeneration of cardiac repair after acute myocardial infarction

Acute myocardial infarction (AMI) has been treated via injectable hydrogels and biomaterial patches invented using tissue engineering advancements over the past decade. Yet the curative potential of injectable hydrogels and stem cells is limited. Here, we propose the development of an injectable and conductive hydrogel composed of oxidised macromolecular hyaluronic acid and chitosan-grafted aniline tetramer polymeric components. In an attempt to enhance the therapeutic potential of AMI therapy, mesenchymal stem cells derived from human umbilical cord blood (HUCB-MSC) have been integrated into the formulation of a conductive hydrogel. For reliable connection to the beating hearts, the hydrogel exhibited suitable adhesive properties. Hydrogel’s potent biocompatibility was determined by in vitro investigations of cell viability and proliferation of NRCMs and H9C2 cardiomyocytes. After myocardial injection, longer HUCB-MSCs survival length, cardiac functioning, and histology in SD rat myocardium were demonstrated, greatly associated by up-regulation and downregulation of cardiac-related relative gene expressions of angiogenic factors and inflammatory factors, respectively. The injectable hydrogel that contained HUCB-MSCs substantially enhanced the therapeutic benefits, indicating a potentially beneficial therapeutic approach to AMI therapy.

Unravelling the oxygen factor - An investigation of transcriptional activation of hypoxia associated placental angiogenesis in recurrent pregnancy loss (RPL) patients from Assam, India

IntroductionRecurrent pregnancy loss (RPL) is defined as the spontaneous loss of two or more consecutive pregnancies before 20 weeks of gestation, and affects 7.46 % of the Indian population. About 40–50 % of RPL cases are idiopathic making it a therapeutic challenge for clinicians. This study focuses on elucidating the role of hypoxia-associated placental angiogenesis in these idiopathic RPL cases. MethodsWhole blood and product of conception (POCs) were collected from RPL patients (N = 87) and cases of voluntary abortions (medically terminated pregnancy, MTP; n = 110) as controls with informed consent. Serum separated from whole blood was used to study the ROS-antioxidant status in the cases and controls through colorimetric assays and ELISA. The mRNA extracted from placental tissue samples were used to determine the hypoxic and angiogenic status in cases and controls through real time PCR. Statistical analysis was also carried out to correlate the differential hypoxic status between RPL and MTP cohorts with the expression of angiogenic factors (VEGFA, VEGFR1 and VEGFR2). ResultsHIF1α mRNA expression was found to be upregulated in the RPL cases. While the serum levels of H2O2 (p = 0.012), guanine oxides and lipid hydroperoxides (LPO) were increased in the RPL cases, reduced glutathione (GSH) was found to be significantly decreased (p = 0.012). Additionally, AUROC analysis also shows an excellent discriminatory ability of 0.850 for serum H2O2 levels. VEGF-A and VEGF-R1 mRNA expression was also found to be downregulated in the RPL cases compared to MTP. DiscussionThis study indicates that increased oxidative stress may lead to aberrations in the VEGF pathway resulting in improper placentation in RPL cases, and subsequently, pregnancy loss.

Intrathecal Fumagillin Alleviates Chronic Neuropathy-Induced Nociceptive Sensitization and Modulates Spinal Astrocyte-Neuronal Glycolytic and Angiogenic Proteins.

Nociceptive sensitization is accompanied by the upregulation of glycolysis in the central nervous system in neuropathic pain. Growing evidence has demonstrated glycolysis and angiogenesis to be related to the inflammatory processes. This study investigated whether fumagillin inhibits neuropathic pain by regulating glycolysis and angiogenesis. Fumagillin was administered through an intrathecal catheter implanted in rats with chronic constriction injury (CCI) of the sciatic nerve. Nociceptive, behavioral, and immunohistochemical analyses were performed to evaluate the effects of the inhibition of spinal glycolysis-related enzymes and angiogenic factors on CCI-induced neuropathic pain. Fumagillin reduced CCI-induced thermal hyperalgesia and mechanical allodynia from postoperative days (POD) 7 to 14. The expression of angiogenic factors, vascular endothelial growth factor (VEGF) and angiopoietin 2 (ANG2), increased in the ipsilateral lumbar spinal cord dorsal horn (SCDH) following CCI. The glycolysis-related enzymes, pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA) significantly increased in the ipsilateral lumbar SCDH following CCI on POD 7 and 14 compared to those in the control rats. Double immunofluorescence staining indicated that VEGF and PKM2 were predominantly expressed in the astrocytes, whereas ANG2 and LDHA were predominantly expressed in the neurons. Intrathecal infusion of fumagillin significantly reduced the expression of angiogenic factors and glycolytic enzymes upregulated by CCI. The expression of hypoxia-inducible factor-1α (HIF-1α), a crucial transcription factor that regulates angiogenesis and glycolysis, was also upregulated after CCI and inhibited by fumagillin. We concluded that intrathecal fumagillin may reduce the expression of ANG2 and LDHA in neurons and VEGF and PKM2 in the astrocytes of the SCDH, further attenuating spinal angiogenesis in neuropathy-induced nociceptive sensitization. Hence, fumagillin may play a role in the inhibition of peripheral neuropathy-induced neuropathic pain by modulating glycolysis and angiogenesis.

Effect of diabetes on hypoxic microvascular remodeling and muscle damage in chronic limb threatening ischemia

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Finnish Academy/Research Council of Finland. The Finnish Foundation for Cardiovascular Research Background Hypoxia-induced arterialization of skeletal muscle capillaries has recently been identified as an important pathological feature that aggravates ischemic damage in chronic limb threatening ischemia (CLTI). Diabetes is also known to worsen the outcome of CLTI patients but its contribution to capillary arterialization and skeletal muscle pathology under ischemia is still largely unknown. Purpose To study how diabetes affects capillary arterialization and skeletal muscle pathology in CLTI. Methods Amputation muscle samples from CLTI patients (n=21 patients x3 samples) were histologically analyzed, grouped according to microvascular changes and RNA sequencing was performed. Differentially expressed genes, differentially regulated signaling pathways and histology between diabetics and non-diabetics were studied among corresponding microvascular groups. Also, spatial transcriptomics (n=2 patients) was applied to understand the mechanisms through which diabetes alters differential capillary responses on the tissue level. Results Diabetes differentially regulated gene expression of different angiogenic and arteriogenic factors including HIF1A, VEGFA, FLT1, NOTCH1, NOTCH3, NOS1 and ITGB3 in the CLTI muscles. This differential transcriptomic regulation translated as increased sprouting on the level of muscle capillaries, and also affected myofiber pathology. Muscle samples in diabetic patients often presented myofiber swelling and cell death that were uncommon in samples of non-diabetic patients. Conclusion Diabetic patients on the level of muscle transcriptional regulation show changes that can explain observed differential microvascular remodeling and worsened myofiber pathology. These results broaden our understanding of the causes for the exceptionally bad outcome of diabetics among CLTI patients.