Diabetic retinopathy (DR) is the leading cause of blindness in the working-age population in developed countries, and its prevalence will increase as the global incidence of diabetes grows ...exponentially. DR begins with an early nonproliferative stage in which retinal blood vessels and neurons degenerate as a consequence of chronic hyperglycemia, resulting in vasoregression and persistent retinal ischemia, metabolic disequilibrium, and inflammation. This is conducive to overcompensatory pathological neovascularization associated with advanced proliferative DR. Although DR is considered a microvascular complication, the retinal microvasculature is intimately associated with and governed by neurons and glia; neurodegeneration, neuroinflammation, and dysregulation of neurovascular cross talk are responsible in part for vascular abnormalities in both early nonproliferative DR and advanced proliferative DR. Neuronal activity directly regulates microvascular dilation and blood flow in the process of neurovascular coupling. Retinal neurons also secrete guidance cues in response to injury, ischemia, or metabolic stress that may either promote or suppress vascular outgrowth, either alleviating or exacerbating DR, contingent on the stage of disease and retinal microenvironment. Neurodegeneration, impaired neurovascular coupling, and dysregulation of neuronal guidance cues are key events in the pathogenesis of DR, and correcting these events may prevent or delay development of advanced DR. The review discusses the mechanisms of neurovascular cross talk and its dysregulation in DR, and their potential therapeutic implications.
The ephemerality of the maturing follicle and subsequent corpus luteum as they perform their gametogenic and/or endocrine functions during the ovarian cycle is associated with remarkable changes in ...local vasculature. Studies on the angiogenic and angiolytic process in the ovary, rare in healthy adult tissues, complement recent efforts to understand vasculogenesis in embryonic tissues and to control angiogenesis in pathologic states such as cancer. Several reports indicate that the newly discovered vascular-specific angiogenic factors are expressed in the ovary, notably members of the vascular endothelial growth factor (VEGF) and angiopoietin (Ang) families plus their receptors (VEGF-Rs, neuropilins, Tie). Unlike in many other tissues, gonadotropic hormones (particularly luteinizing hormone, LH) are major stimulators of angiogenesis and VEGF/Ang expression in the ovary. However, local factors such as insulin-like growth factors or oxygen tension likely modulate the angiogenic processes. Recent studies employing systemic or local administration of anti-angiogenic drugs (TNP-470 or fumagillin) or specific VEGF antagonists (VEGF antibody or soluble VEGFR-1) demonstrate a vital role for normal angiogenesis and VEGF action in follicle development, ovulation, or corpus luteum function. Further studies discerning the various angiogenic factors and their roles in controlling the growth, maturation, function, and regression of the vasculature in ovarian compartments during the menstrual cycle could yield novel strategies for manipulating fertility or for alleviating infertility.
Diabetes mellitus (DM) is a chronic metabolic disease characterized by the presence of hyperglycemia, which can lead to many complications over time. These complications, such as nephropathy, ...retinopathy, neuropathy, impaired wound healing and accelerated atherosclerosis, are implicated with a large number of cellular and subcellular changes on vessels. In agreement, evidence indicates that in retinopathy, nephropathy and atherosclerotic plaque, there is excessive angiogenesis, whereas in wound healing and myocardial perfusion, blood vessel growth is impaired. Despite the awareness of this angiogenic paradox, many questions remain unanswered. This review aims at highlighting the different microvascular and macrovascular complications that are often concurrent in diabetic patients. A revision of the recent findings published in the literature regarding the angiogenic paradox will be performed. Apparently, endothelial dysfunction, as well as molecules such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF) play a major role in diabetic vascular complications. Specific tissues with impaired angiogenesis exhibit microenvironment features, such as increased PAI-1/uPA ratio and decreased blood flow, whereas TGFbeta increases extracellular matrix deposition, preventing the vascularization process. In addition, the monocytes/macrophages are important in endothelium activation for arteriogenesis and its arteriogenic response is reduced, leading to impaired collateral artery growth. Moreover, molecular mechanisms involved will be addressed, including abnormalities in growth factor, cytokines and metabolic derangements.
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Three populations of myogenic cells were isolated from normal mouse skeletal muscle based on their adhesion characteristics and proliferation behaviors. Although two of these populations displayed ...satellite cell characteristics, a third population of long-time proliferating cells expressing hematopoietic stem cell markers was also identified. This third population comprises cells that retain their phenotype for more than 30 passages with normal karyotype and can differentiate into muscle, neural, and endothelial lineages both in vitro and in vivo. In contrast to the other two populations of myogenic cells, the transplantation of the long-time proliferating cells improved the efficiency of muscle regeneration and dystrophin delivery to dystrophic muscle. The long-time proliferating cells' ability to proliferate in vivo for an extended period of time, combined with their strong capacity for self-renewal, their multipotent differentiation, and their immune-privileged behavior, reveals, at least in part, the basis for the improvement of cell transplantation. Our results suggest that this novel population of muscle-derived stem cells will significantly improve muscle cell-mediated therapies.
Objective
Determine the effect of bradykinin on solute permeability and cellular junctional proteins in human dermis microvascular endothelial cells.
Methods
Cells were characterized by ...immunofluorescence and fluorescence‐activated cell sorting. Macromolecular transport of dextran and albumin was monitored. Junctional protein expression and phosphorylation were determined by immunoblot analyses. Intracellular calcium and cAMP levels were evaluated. Target gene expression at mRNA and protein levels was determined.
Results
Human dermis microvascular endothelial cells comprised 97% lymphatic endothelial cells. Bradykinin increased the permeability to dextran in a concentration‐dependent manner, while reduced the permeability to albumin. Bradykinin treatment down‐regulated VE‐cadherin expression and affected its phosphorylation status at Tyr731. It also down‐regulated claudin‐5 expression at the transcriptional level through bradykinin‐2‐receptor signaling. An increase in the intracellular calcium levels and a reduction in the cAMP concentration were associated effects. Finally, bradykinin induced the up‐regulation of vascular endothelial growth factor‐C protein which was found increased in BK‐induced human dermis microvascular endothelial cells culture supernates.
Conclusions
Human dermis microvascular endothelial cells represent a model of lymphatic endothelial cells, in which bradykinin‐2‐receptor is expressed. Bradykinin‐induced bradykinin‐2‐receptor signaling through intracellular calcium mobilization and reduction in cAMP levels, triggered changes in solute permeability and cellular junction expression. It further up‐regulated vascular endothelial growth factors‐C protein expression, which is a key modulator of lymphatic vessels function and lymphangiogenesis.
Vascular endothelial growth factor (VEGF) plays an essential role in the angiogenesis of growing cartilage. Although VEGF expression in cartilage vanishes in normal adults, VEGF is known to be ...expressed in chondrocytes of osteoarthritic (OA) cartilage. As little information is available on the VEGF expression in the cartilage of OA-like lesions of the temporomandibular joint (TMJ), VEGF expression in the condylar cartilage of TMJs of rats affected with OA was examined. To evoke OA, mechanical stress was applied by forced jaw opening for 10 or 20 days. After 20 days, marked OA-like lesions were observed in the condyle. VEGF was expressed in the chondrocytes of the mature and hypertrophic cell layers of the intermediate and posterior region of the condyle. The percentage of VEGF immunopositive chondrocytes significantly increased with the period of applied mechanical stress. Furthermore, tartrate-resistant acid phosphatase (TRAP) staining of the condylar cartilage showed significant increment of osteoclasts in the mineralized layer subjacent to the hypertrophic layer where high VEGF expression could be detected. The results suggest that VEGF plays an important role in the progression of OA.
Purpose: Ranibizumab, an anti-VEGF-A (vascular endothelial cell growth factor-A) monoclonal antibody fragment, is a well-established treatment for diabetic patients with macular edema. However, very ...little is known about the effect of ranibizumab on intraocular regulation of pro - and anti-inflammatory signaling pathways and their regulation of VEGF family members, which was the aim of this study.
Materials and Methods: Diabetic patients (n = 10) aged ≥18 years with central diabetic macular edema, BCVA >24 and <78, and central macular thickness (CMT) greater than 250 μm were enrolled in this study. Following a full eye exam, imaging, and an aqueous tap, patients received ranibizumab (0.3 mg/0.05 mL) injections at day one and weeks four and eight. At week 12, a full eye exam, imaging, and a second aqueous tap was obtained prior to the last injection of ranibizumab. Pre - and post-treatment aqueous humor samples were then analyzed using Milliplex MAP magnetic bead assays.
Results: As expected, ranibizumab lowered levels of VEGF-A, decreased CMT, and improved VA (visual acuity). In addition, it significantly lowered aqueous levels of IL-10, IFNγ, sIL-1R1, sIL-1R2, sRAGE, and VEGF-D. Changes in levels of VEGF-A and VEGF-C strongly correlated with changes in soluble receptors, sgp130 and sIL-6R, associated with IL-6 signaling pathways. In contrast, changes in VEGF-D correlated with sIL-1R1 and sIL-1R2, soluble receptors participating in IL-1 signaling. Changes in CMT and VA did not correlate with changes in levels of VEGF family members. However, post-treatment values of CMT correlated with post-treatment levels of VEGF-C. Post-treatment VA values correlated with a wide variety of potential biomarkers linked to inflammation.
Conclusions: Ranibizumab treatment had strong effects on regulating levels of soluble receptors closely linked to IL-1 and IL-6 signaling pathways. Therefore, a complete understanding of the actions of ranibizumab will further the development of additional therapies to support treatment of diabetic macular edema.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The signalling cascade including Raf, mitogen-activated protein kinase (MAPK) kinase and extracellular-signal-regulated kinase (ERK) is important in many facets of cellular regulation. Raf is ...activated through both Ras-dependent and Ras-independent mechanisms, but the regulatory mechanisms of Raf activation remain unclear. Two families of membrane-bound molecules, Sprouty and Sprouty-related EVH1-domain-containing protein (Spred) have been identified and characterized as negative regulators of growth-factor-induced ERK activation. But the molecular functions of mammalian Sproutys have not been clarified. Here we show that mammalian Sprouty4 suppresses vascular epithelial growth factor (VEGF)-induced, Ras-independent activation of Raf1 but does not affect epidermal growth factor (EGF)-induced, Ras-dependent activation of Raf1. Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4. In addition, Sprouty4 mutants of the amino-terminal region containing the conserved tyrosine residue, which is necessary for suppressing fibroblast growth factor signalling, still inhibit the VEGF-induced ERK pathway. Our results show that receptor tyrosine kinases use distinct pathways for Raf and ERK activation and that Sprouty4 differentially regulates these pathways.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Catheter-based intracoronary vascular endothelial growth factor (VEGF) gene transfer is a potential treatment for coronary heart disease. However, only limited data are available about local VEGF ...gene transfer given during angioplasty (PTCA) and stenting.
Patients with coronary heart disease (n=103; Canadian Cardiovascular Society class II to III; mean age, 58+/-6 years) were recruited in this randomized, placebo-controlled, double-blind phase II study. PTCA was performed with standard methods, followed by gene transfer with a perfusion-infusion catheter. Ninety percent of the patients were given stents; 37 patients received VEGF adenovirus (VEGF-Adv, 2x10(10) pfu), 28 patients received VEGF plasmid liposome (VEGF-P/L; 2000 microg of DNA with 2000 microL of DOTMA:DOPE 1:1 wt/wt), and 38 control patients received Ringer's lactate. Follow-up time was 6 months. Gene transfer to coronary arteries was feasible and well tolerated. The overall clinical restenosis rate was 6%. In quantitative coronary angiography analysis, the minimal lumen diameter and percent of diameter stenosis did not significantly differ between the study groups. However, myocardial perfusion showed a significant improvement in the VEGF-Adv-treated patients after the 6-month follow-up. Some inflammatory responses were transiently present in the VEGF-Adv group, but no increases were detected in the incidences of serious adverse events in any of the study groups.
Gene transfer with VEGF-Adv or VEGF-P/L during PTCA and stenting shows that (1) intracoronary gene transfer can be performed safely (no major gene transfer-related adverse effects were detected), (2) no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up, and (3) a significant increase was detected in myocardial perfusion in the VEGF-Adv-treated patients.
To evaluate the role of prophylactic propranolol in the prevention of retinopathy of prematurity (ROP) in infants ≤32 weeks of gestational age and their visual outcome at 1 year of corrected ...gestational age.
Randomised double blind placebo controlled trial, parallel group nrolment with allocation ratio of 1:1.
Two level III neonatal intensive care units.
109 preterm neonates of ≤32 weeks of gestation with postnatal age ≤8 days old.
Infants with gestational age between 26 and 32 weeks were started on propranolol prophylaxis (0.5 mg/kg/dose every 12 hours) on seventh completed day of life, till a corrected gestational age of 37 weeks or complete vascularisation of retina whichever was later.
infants received a placebo.
: ROP of all grades;
: evaluation of complications due to propranolol, ROP needing treatment with laser and/or antivascular endothelial growth factor (anti-VEGF) and visual outcome at 12 months corrected age.
Prophylactic propranolol in the prescribed dose of 1 mg/kg/day showed a decreasing trend in the incidence of ROP (56.8% vs 68.6%; p=0.39), need for laser therapy (21.56% vs 31.37%; p=0.37), treatment with anti-VEGF (3.92% vs 15.68%; p=0.09) or visual outcomes at 1 year in the study and control groups, respectively, though these reductions were not statistically significant. Decreasing trends favouring propranolol in all other ROP-related outcomes were also noted in the study group.
Prophylactic propranolol in the prescribed dose of 1 mg/kg/day showed a decreasing trend in all outcomes of ROP though statistically not significant.
CTRI/2013/11/004131.
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