During osteoarthritis (OA), angiogenesis is increased in the synovium, osteophytes and menisci and leads to ossification in osteophytes and the deep layers of articular cartilage. Angiogenic and antiangiogenic factors might both be upregulated in the osteoarthritic joint; however, vascular growth predominates, and the articular cartilage loses its resistance to vascularization. In addition, blood vessel growth is increased at--and disrupts--the osteochondral junction. Angiogenesis in this location is dependent on the creation of channels from subchondral bone spaces into noncalcified articular cartilage. Inflammation drives synovial angiogenesis through macrophage activation. Blood vessel and nerve growth are linked by common pathways that involve the release of proangiogenic factors, such as vascular endothelial growth factor, β-nerve growth factor and neuropeptides. Proangiogenic factors might also stimulate nerve growth, and molecules produced by vascular cells could both stimulate and guide nerve growth. As sensory nerves grow along new blood vessels in osteoarthritic joints, they eventually penetrate noncalcified articular cartilage, osteophytes and the inner regions of menisci. Angiogenesis could, therefore, contribute to structural damage and pain in OA and provide potential targets for new treatments.

Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis

https://cyberleninka.org/article/n/106406.pdf

Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms.

Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy

Glaucoma is an age related heterogeneous group of diseases affecting 70 million people worldwide that is commonly associated with elevated intraocular pressure due to impairment of the outflow pathway of the trabecular meshwork, and characterized by pathological changes in optic nerve head, and lamina cribosa, leading to visual field defects and eventual blindness due to apoptosis of retinal ganglion cells (RGCs) (Clark and Yorio, 2003; Fraser and Wormald, 1999; and Lipton, 2003). The predominant risk factor for patients that suffer from glaucoma is elevation of intraocular pressure (IOP) (Fatma, et al. 2008). Elevated IOP imposes strain on the unmyelinated portion of axons of the RGCs, at the optic nerve head where they take a 90 degree turn to traverse to their final destination at the lateral geniculate nucleus in the thalamus of the brain, or to the superior colliculus in lower vertebrate animals (Quigley 1981). This strain on the axons of the RGCs at the optic nerve head is thought to be the initiating primary insult that damages the axons of the RGCs, inhibiting retrograde transport of neurotrophic factors produced in the brain, and eventually leading to cell death of RGCs (Quigley 1981). This primary insult is hypothesized to initiate a release of noxious secondary factors including glutamate, endothelin, and tumor necrosis-factor-α from injured RGCs and proliferating astrocytes going through reactive gliosis (Clark and Yorio 2003; Prasanna et al., 2010; Tezel and Wax, 2000; Tezel et al., 2001; Tezel and Wax 2004; Nakazawa et al. 2006). These secondary factors are also hypothesized to be associated with RGC death. Other mechanisms include ischemia/hypoxia at the optic nerve head, which could trigger release of glutamate, endothelin-1 (ET-1) and TNF-α from astrocytes, which could contribute to neurodegeneration. Currently used treatment modalities for glaucoma are agents targeted at lowering IOP and preventing the primary insult contributing to RGC apoptosis. If the main cause of RGC death is axotomy due to pressure induced trauma to axons at the optic nerve head, then a reduction of IOP should protect the remainder of RGCs and halt the progression of this disease process. Although IOP in glaucoma patients is often held within “normal” ranges, the disease process and RGC death can still progress. Additionally, patients with IOP measurements of 6-10 mmHg (normal being 10-20 mmHg) can still develop glaucoma (normal tension glaucoma), thus suggesting that elevation of IOP is not the only predisposing factor for patients that suffer from glaucoma, and suggests that there may be

/pdf/neuroprotection-in-glaucoma-1kufo5989b.pdf

Neuroprotection in Glaucoma

Diabetes mellitus is associated with an increased risk of cardiovascular disease due to its negative impact on the vascular endothelium. The damaged endothelium is repaired by resident cells also through the contribution of a population of circulating cells derived from bone marrow. These cells, termed endothelial progenitor cells (EPCs) are involved in maintaining endothelial homeostasis and contributes to the formation of new blood vessels with a process called postnatal vasculogenesis. The mechanisms whereby these cells allow for protection of the cardiovascular system are still unclear; nevertheless, consistent evidences have shown that impairment and reduction of EPCs are hallmark features of type 1 and type 2 diabetes. Therefore, EPC alterations might have a pathogenic role in diabetic complications, thus becoming a potential therapeutic target. In this review, EPC alterations will be examined in the context of macrovascular and microvascular complications of diabetes, highlighting their roles and functions in the progression of the disease.

Endothelial progenitor cells in diabetes mellitus

Diabetic retinopathy is characterized by pathological retinal neovascularization. Accumulating evidence has indicated that high levels of circulating endothelial progenitor cells (EPCs) are an important risk factor for neovascularization. Paradoxically, the reduction and dysfunction of circulating EPCs has been extensively reported in diabetic patients. We hypothesized that EPCs are differentially altered in the various vasculopathic complications of diabetes mellitus, exhibiting distinct behaviors in terms of angiogenic response to ischemia and growth factors and potentially playing a potent role in motivating vascular precursors to induce pathological neovascularization. Circulating levels of EPCs from diabetic retinopathy patients were analyzed by flow cytometry and by counting EPC colony-forming units, and serum levels of neurotrophic factors were measured by enzyme-linked immunosorbent assay. We found increased levels of nerve growth factor and brain-derived neurotrophic factor in the blood of diabetic retinopathy patients; this increase was correlated with the levels of circulating EPCs. In addition, we demonstrated that retinal cells released neurotrophic factors under hypoxic conditions to enhance EPC activity in vitro and to increase angiogenesis in a mouse ischemic hindlimb model. These results suggest that neurotrophic factors may induce neoangiogenesis through EPC activation, leading to the pathological retinal neovascularization. Thus, we propose that neovascularization in the ischemic retina might be regulated by overexpression of neurotrophic factors.

Endothelial progenitor cells (EPCs) mobilized and activated by neurotrophic factors may contribute to pathologic neovascularization in diabetic retinopathy.

PURPOSE. To evaluate the role of nerve growth factor (NGF) in retinal neovascularization in an oxygen-induced retinopathy (OIR) model. METHODS. The OIR model was established in C57BL/6J mice. NGF mRNA expression in retina was measured by quantitative real-time PCR. NGF expression in protein levels was evaluated by ELISA and immunostaining with NGF antibody. The effects of NGF on retinal neovascularization were evaluated by intravitreal injections of exogenous NGF and TrkA receptor inhibitor K252a, respectively, in an OIR model. Retinal neovascularization was measured by counting neovascular cell nuclei above the internal limiting membrane and by image quantification analysis in flat-mounted retinas perfused with fluorescein dextran. RESULTS. NGF mRNA in retina had significantly high expression at postnatal day (P)17 in the OIR model compared with normally developing mice. Similarly, ELISA and immunostaining assay showed significantly increased NGF expression in retina at P17 in OIR mice but no significant differences at P12 or P24 compared with normal controls. Exogenous NGF intraocular injection enhanced angiogenesis in the retina in the OIR model; however, injection with K252a, a high-affinity trkA receptor inhibitor, significantly decreased retinal neovascularization compared with that seen in the controls. CONCLUSIONS. NGF contributed to retinal neovascularization in the OIR model. Intravitreal injection with K252a, the trkA receptor inhibitor, reduced neovascularization, showing the potential therapeutic efficacy of NGF receptor inhibitor in OIR mice.

Neuronal-driven angiogenesis: role of NGF in retinal neovascularization in an oxygen-induced retinopathy model.

Aims To investigate the correlation between the retinal microvasculature using optical coherence tomography angiography (OCTA) and systemic factors in type 2 diabetes mellitus (T2DM) patients. Methods This cross-sectional study obtained OCTA data from patients with T2DM administered at hospital and referred to ophthalmic services. Patient data about demographics, comorbid conditions, and blood biomarkers were extracted from electronic medical records. Data from OCTA scans obtained by CIRRUS HD-OCT Model 5,000 were obtained. Vessel density (VD) and perfusion density (PD) within the superficial capillary plexus, and foveal avascular zone (FAZ) area were automatically segmented. These parameters were tested for their correlations with systemic factors by univariate and multivariable linear regression analyses. Results A total of 144 T2DM patients (236 eyes) were available for analysis, with mean age of 53.6 (SD = 10.34) and 56.9% were male. Chronic kidney disease, cardiovascular disease, increased serum creatinine (Scr), red blood cell count (RBC), platelets (PLT), apolipoprotein B (APOB), and decreased urine albumin to creatinine ratio (UACR) were significantly associated with lower VD and PD (all p < 0.013). UACR and triglyceride (TRIG) were significantly correlated with FAZ area (all p < 0.017). In multivariate analyses, PLT, eGFR, and APOB were independent risk factors for retinal rarefaction, and UACR was a significant predictor of FAZ area. Conclusion We found several systemic risk factors, such as PLT, renal function and lipid profiles were associated with PD, VD, and FAZ area among Chinese T2DM patients.

/pdf/the-association-between-retinal-microvasculature-derived-5c13ihb6.pdf

The association between retinal microvasculature derived from optical coherence tomography angiography and systemic factors in type 2 diabetics

Background Retinal ganglion cells (RGCs) axon loss at the site of optic nerve head (ONH) is long believed as the common pathology in glaucoma since different types of glaucoma possessing different characteristic of intraocular pressure, and this damage was only detected at the later stage. Methods To address these disputes and detect early initiating events underlying RGCs, we firstly detected somatic or axonal change and compared their difference in acute and chronic phase of primary angle-closed glaucoma (PACG) patient using optical coherence tomography (OCT), then an axonal-enriched cytoskeletal protein neurofilament heavy chain and its phosphoforms (NF-H, pNF-H) were utilized to reveal spatio-temporal undetectable damage insulted by acute and chronic ocular hypertension (AOH, COH) in two well characterized glaucoma mice models. Results In clinic, we detected nonhomogeneous changes such as ONH and soma of RGCs presenting edema in acute phase but atrophy in chronic one by OCT. In AOH animal models, an increase expression of NF-H especially its phosphorylation modification was observed as early as 4 h before RGCs loss, which presented as somatic accumulation in the peripheral retina and at the sites of ONH. In contrast, in microbeads induced COH model, NF-H and pNF-H reduced significantly, these changes firstly occurred as NF-H or pNF-H disconnection at ONH and optic nerve after 2 weeks when the intraocular pressure reaching the peak; Meanwhile, we detected aqueous humor pNF-H elevation after AOH and slight reduction in the COH. Conclusion Together, our data supports that early alteration of NF-H and its phosphoforms would reveal undetectable subcellular damage consisting of peripheral somatic neurofilament compaction, impaired axonal transport and distal axonal disorganization of cytoskeleton beyond the ONH, and identifies two distinct axonal degeneration which were Wallerian combination with retrograde degeneration in acute PACG and retrograde degeneration in the chronic one.

/pdf/alteration-of-neurofilament-heavy-chain-and-its-phosphoforms-1qgtzv33.pdf

Alteration of neurofilament heavy chain and its phosphoforms reveals early subcellular damage beyond the optic nerve head in glaucoma

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Endothelial progenitor cells (EPCs) mobilized and activated by neurotrophic factors may contribute to pathologic neovascularization in diabetic retinopathy.

Neuronal-driven angiogenesis: role of NGF in retinal neovascularization in an oxygen-induced retinopathy model.

The association between retinal microvasculature derived from optical coherence tomography angiography and systemic factors in type 2 diabetics

Alteration of neurofilament heavy chain and its phosphoforms reveals early subcellular damage beyond the optic nerve head in glaucoma