Elevated Vascular Endothelial Growth Factor Research Articles

Metabolic consequences of lactate dehydrogenase inhibition by oxamate in hyperglycemic proximal tubular cells

Diabetic kidney disease (DKD) is associated with altered metabolic patterns, leading to increased lactate production even in the presence of sufficient oxygen supply. Studies have shown hyperglycemia to be an important factor in determining development of DKD.Here we explore the metabolic consequences of lactate dehydrogenase (LDH) inhibition exerted by the LDH inhibitor, oxamate, in the isolated rat renal proximal tubular cells (NRK-52E) under hyperglycemic conditions.Cells treated with oxamate (100 mM) for 24 h, with or without high D-glucose (25 mM) load, were investigated with hyperpolarized [1-13C]pyruvate in a 1T NMR system. Respiratory measurements using an oxygen microsensor system was conducted.Oxamate treatment of cells with or without the presences of high D-glucose, reduced the lactate production/accumulation with 36.5% or 22.5% respectively. Reduced proliferation, hypertrophic effects, as well as elevated vascular endothelial growth factor (VEGF) expression in the NRK-52E cells were found. The increased glycolytic flux in high D-glucose cultured NRK-52E cells resulted in an upregulation of the cellular oxygen consumption rate upon treatment with oxamate.Our findings suggested that in vitro cultured NRK-52E cells exposed to hyperglycemic conditions, could redirect the glycolytic flux towards oxidative phosphorylation by LDH inhibition. This link between aerobic and anaerobic metabolism may be determined by the redox balance (NAD+/NADH ratio). In conclusion, hyperglycemic conditions and oxamate treatment alters the metabolic phenotype of NRK-52E cells towards increased oxygen utilization mediated by a decreased NAD+/NADH ratio, which in turn decreases cell proliferation/survival.

Clinical characteristics and the long-term outcome of patients with atypical POEMS syndrome variant with undetectable monoclonal gammopathy.

The diagnosis of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome requires polyneuropathy and monoclonal plasma cell proliferation as two mandatory criteria. Our aim was to summarize clinical manifestations and treatment responses of POEMS variants with no evidence of monoclonal gammopathy. We queried all medical documentation of patients referred to Peking Union Medical College Hospital from August 2012 to July 2017, and reviewed the clinical and laboratory features of 13 patients with atypical POEMS syndrome with undetectable monoclonal gammopathy, and compared to prototypes published. The prevalence of polyneuropathy, organomegaly, skin changes, and extravascular fluid overload were 100%, 100%, 92%, and 100%, respectively. Other clinical manifestations, such as endocrinopathy, pulmonary hypertension, papilledema, thrombocytosis, and polycythemia affected similar percentages of patients as seen in prototypes. POEMS variants enrolled had a median serum vascular endothelial growth factor (VEGF) level of 4998pg/ml (range 2155-11,029pg/ml). Long-term follow-up found that all 12 patients received autologous stem cell transplant, melphalan-based therapy or lenalidomide/thalidomide-based therapy obtained clinical improvement, of which eight experienced decreased levels of VEGF by 50% or back to normal. The median progression-free survival was 101.5months. Our findings raised a variant of POEMS syndrome variants with featured clinical manifestations, elevated VEGF levels, and good response to therapies targeting plasma cell.

Elevated Vascular Endothelial Growth Factor Level in Association with Mean Platelet Volume Are Emerging Risk Factors for Vascular Complications in T2DM Patients

Increasing evidence in both experimental and clinical studies suggests oxidative stress (OS) plays a major role in the pathogenesis of type 2 diabetes mellitus and its complications. In a physiological condition, appropriate levels of ROS, generated either in restricted amounts or transient fashion, are required to promote physiological angiogenesis and homeostatic maintenance of healthy vasculature. Uncontrolled continuous ROS production will ultimately contribute to pathology and cause tissue damage. One of the most important proangiogenic factors is vascular endothelial growth factor (VEGF) which plays a key role in diabetic endothelial dysfunction, which ultimately leads to pathogenesis of vascular complications. As VEGF is released by activated platelets, hence platelet activation could be the source of VEGF in plasma samples. Increased platelet activity is emphasized to play a role in the development of vascular complications in T2DM patients and platelet volume, a marker of the platelet function and activation, is measured as mean platelet volume (MPV). Therefore, we aimed to investigate the association between plasma VEGF levels and MPV levels that may lead to vascular complications. A case-control study of one hundred patients with T2DM (n = 100) and thirty control subjects (n = 30) were screened from different areas of West Bengal. All procedures were done with the informed consent of participants. Elevated VEGF level was found in T2DM patients (526.8 ± 34.3 pg/ml) compared to healthy controls (317.9 ± 12.9 pg/ml) which was statistically significant. T2DM patients had higher MPV (12.5 ± 0.2 fl) compared to controls (11.4 ± 0.2 fl). Thus the present study showed a significant association between VEGF level in plasma and MPV indicating the severity of vascular complications. Hence, in conclusion, it suggested that VEGF levels along with MPV are a reliable biomarker for evaluating the development and progression of vascular complications.

POEMS syndrome: advances in molecular pathophysiology and treatment

POEMS syndrome is a rare paraneoplastic disorder characterized by polyneuropathy, organomegaly, endocrinopathy, λ-type monoclonal protein derived from only two germlines (IGLV1-40 or IGLV1-44), skin changes, extravascular volume overload, and serum vascular endothelial growth factor elevation. To understand the molecular pathophysiology of the disease, comprehensive genetic analyses of bone marrow plasma cells was performed in 20 patients with the syndrome. Although a median of 14.5 mutated genes were identified per patient, none of the driver gene mutations frequently found in multiple myeloma were detected. RNA sequencing revealed a transcription profile specific to POEMS syndrome, which suggested that the genetic and transcriptional profiles of plasma cells in POEMS syndrome are distinct from multiple myeloma and monoclonal gammopathy of undetermined significance. Treatment strategies for the devastating disease have been developed by targeting monoclonal plasma cells with novel agents, mainly thalidomide, followed by autologous stem cell transplantation (ASCT). Moreover, the 5-year overall survival after ASCT has improved to as high as 90% with dramatic improvement in symptoms and activities of daily living. However, the 5-year progression-free survival during long-term follow-up has dropped to 60%. Therefore, identifying novel therapeutic targets are imperative for further improvement of disease outcomes.

The potential effect of human chorionic gonadotropin on vasoproliferative disorders of the immature retina.

Human chorionic gonadotropin (hCG) is known to be a powerful vascular endothelial growth factor (VEGF)-regulating hormone. It stimulates vascularization of the gravid uterus by upregulating VEGF expression. In the body, hCG activates the same receptor as luteinizing hormone (LH). Like hCG, LH is also strongly proangiogenic. Recently, it has been shown that LH/hCG receptors are present in the retina and that both LH and hCG are found in the eye. In fact, the human eye can synthesize its own hCG. We have previously shown that LH and VEGF are significantly correlated in mammalian eyes, potentially implicating LH-receptor/hCG-receptor activation in intraocular VEGF regulation. Given that elevated VEGF is associated with progression of two vasoproliferative pediatric retinal disorders, retinopathy of prematurity and retinoblastoma, our objective was to determine whether hCG may potentially affect VEGF production and pathologic retinal vascularization in vasoproliferative disorders affecting the immature retina. In this study, we used (a) oxygen-induced retinopathy mouse model (standard model for retinopathy of prematurity) and (b) Y79 retinoblastoma cells (a human cell line derived from immature retinal cells). In the oxygen-induced retinopathy model, number of preretinal nuclei (representing pathologic retinal neovascularization) significantly increases by 57% (P<0.05) in hCG-treated mice. In Y79 cells, VEGF production significantly increases by 37% (P<0.05) in hCG-treated cells. These findings suggest that hCG is potentially able to influence retinal vascularization and VEGF production and thus, the hCG receptor may potentially represent a therapeutic target for vasoproliferative retinal disorders affecting the young eye.

Clostridium difficile toxins induce VEGF-A and vascular permeability to promote disease pathogenesis.

Clostridium difficile infection (CDI) is mediated by two major exotoxins, toxin A (TcdA) and toxin B (TcdB), that damage the colonic epithelial barrier and induce inflammatory responses. The function of the colonic vascular barrier during CDI has been relatively understudied. Here we report increased colonic vascular permeability in CDI mice and elevated vascular endothelial growth factor A (VEGF-A), which was induced in vivo by infection with TcdA- and/or TcdB-producing C. difficile strains but not with a TcdA-TcdB- isogenic mutant. TcdA or TcdB also induced the expression of VEGF-A in human colonic mucosal biopsies. Hypoxia-inducible factor signalling appeared to mediate toxin-induced VEGF production in colonocytes, which can further stimulate human intestinal microvascular endothelial cells. Both neutralization of VEGF-A and inhibition of its signalling pathway attenuated CDI in vivo. Compared to healthy controls, CDI patients had significantly higher serum VEGF-A that subsequently decreased after treatment. Our findings indicate critical roles for toxin-induced VEGF-A and colonic vascular permeability in CDI pathogenesis and may also point to the pathophysiological significance of the gut vascular barrier in response to virulence factors of enteric pathogens. As an alternative to pathogen-targeted therapy, this study may enable new host-directed therapeutic approaches for severe, refractory CDI.

Expression of Vascular Endothelial Growth Factor in the Gastric Mucosa of Patients with Portal Hypertensive Gastropathy

Background and study aim: Portal hypertensive gastropathy (PHG) is a common finding in patients with cirrhosis and portal hypertension that occurs in between 7% and 98% of cases. High levels of vascular endothelial growth factor (VEGF) in mesentery suggested their contribution in portal hypertension secondary to liver cirrhosis. VEGF participates in regulation of angiogenesis in gastric wall in portal hypertension. The aim was to evaluate the serum concentration of VEGF and gastric mucosal expression of VEGF and its possible association with PHG. Patients and Methods: Serum levels and gastric mucosal expression of VEGF were measured in fifty seven patients with liver cirrhosis and portal hypertensive gastropathy as well as eleven patients with liver cirrhosis without portal hypertensive gastropathy and another twenty one persons served as control group. They were clinically assessed and laboratory investigations were done including liver biochemical profile, and viral markers. Severity of liver disease was assessed by Child-Pugh, model for end stage liver disease (MELD) and updated (uMELD) scores. The presence of PHG was diagnosed by esophago-gastroduodenoscopy. Results: Serum VEGF increased in patients with liver cirrhosis compared to healthy control. But there was no significant difference between patients with PHG and patients without PHG as regard to serum VEGF.VEGF expression in the gastric mucosa was highly significant in patients with PHG than patients without PHG and control group. Serum VEGF has no correlation with severity of liver disease or PHG grade. Conclusion: VEGF was highly expressed in gastric mucosa rather than elevation of serum VEGF in patients with PHG.

A Spectrum of Regression Following Intravitreal Bevacizumab in Retinopathy of Prematurity

To describe an improved understanding of the regression patterns following off-label intravitreal bevacizumab (IVB) treatment for retinopathy of prematurity (ROP). Retrospective cohort study. All infants treated with IVB for type 1 ROP at a single institution from June 2013 to March 2018 were retrospectively reviewed and the amount of retinal nonperfusion on fluorescein angiogram was calculated. In the 92 eyes of 46 patients analyzed, only 3 eyes (3.3%) reached full vascular maturity. Of the 89 eyes not reaching maturity, 39 eyes (43.8%) had vascular arrest alone (VAA), 34 eyes (38.2%) had vascular arrest with persistent tortuosity (VAT), and 16 eyes (18.0%) had ROP reactivation. Those eyes that reactivated were more likely to be initially classified as having aggressive posterior ROP (P= .004) and of Asian ethnicity (P= .008). There were greater areas of ischemia in eyes with reactivation as compared to VAT and VAA (112.1mm2 vs 72.5mm2 vs 56.6mm2, respectively, P= .007). Younger gestational age at birth was found to be an independent predictor of persistent tortuosity (VAT vs VAA) in a logistic regression model. Incomplete vascularization following IVB is very common and is associated with a younger gestational age at birth, Asian ethnicity, and aggressive posterior ROP. The presence of tortuosity following IVB may be indicative of persistently elevated vascular endothelial growth factor levels and an early indicator of potential reactivation.

Salvianolic acid B as an anti-emphysema agent I: In vitro stimulation of lung cell proliferation and migration, and protection against lung cell death, and in vivo lung STAT3 activation and VEGF elevation

Emphysema causes progressive and life-threatening alveolar structural destruction/loss, yet remains irreversible and incurable to date. Impaired vascular endothelial growth factor (VEGF) signaling has been proposed as a new pathogenic mechanism, and if so, VEGF recovery may enable reversal of emphysema. Thus, we hypothesized that salvianolic acid B (Sal-B), a polyphenol in traditional Chinese herbal danshen, is an alveolar structural recovery agent for emphysema by virtue of VEGF stimulation/elevation via activation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), as stimulating lung cell proliferation and migration, and protecting against lung cell death. Using in vitro human lung microvascular endothelial (HMVEC-L) and alveolar epithelial (A549) cell systems, Sal-B was examined for 1) stimulation of cell proliferation by the MTT and BrdU assays; 2) promotion of cell migration by the scratch wound closure assay; 3) protection against emphysema-like induced cell death by the trypan blue exclusion and flow cytometry assays; and 4) mechanistic involvement of JAK2/STAT3/VEGF in these activities. Sal-B was also spray-dosed to the lungs of healthy rats for two weeks to verify the lung's STAT3 activation and VEGF elevation by western blot, as well as the absence of functional and morphological abnormalities. All the in vitro cell-based activities were concentration-dependent. At 25 μM, Sal-B 1) stimulated cell proliferation by 1.4–2.6-fold; 2) promoted migratory cell wound closure by 1.5–1.7-fold; and 3) protected against cell death induced with H2O2 (oxidative stress) and SU5416 (VEGF receptor blockade) by 49–86%. JAK2 and STAT3 inhibitors and VEGF receptor antagonist each opposed these Sal-B's activities by over 65%, suggesting the mechanistic involvement of JAK2/STAT3 activation and VEGF stimulation/elevation. In rats, Sal-B at 0.2 mg/kg enabled 1.9 and 1.5-fold increased STAT3 phosphorylation and VEGF elevation in the lungs, respectively, while causing no functional and morphological abnormalities. Hence, Sal-B was projected to be a new class of anti-emphysema agent capable of reversing alveolar structural destruction/loss via JAK2/STAT3/VEGF-dependent stimulation of lung cell proliferation and migration, and inhibition of induced lung cell death.

Proposal of new clinical diagnostic criteria for POEMS syndrome

ObjectiveTo propose the optimal diagnostic criteria for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome using appropriate statistical methods and disease controls.MethodsThis retrospective cohort study included 104 consecutive patients...

Salvianolic acid B as an anti-emphysema agent II: In vivo reversal activities in two rat models of emphysema

Emphysema progressively destroys alveolar structures, leading to disability and death, yet remains irreversible and incurable to date. Impaired vascular endothelial growth factor (VEGF) signaling is an emerging pathogenic mechanism, thereby proposing a hypothesis that VEGF stimulation/elevation enables recovery from alveolar structural destruction and loss of emphysema. Our previous in vitro study identified that salvianolic acid B (Sal-B), a polyphenol of traditional Chinese herbal danshen, stimulated lung cell proliferation and migration, and protected against induced lung cell death, by virtue of signal transducer and activator of transcription 3 (STAT3) activation and VEGF stimulation/elevation. Thus, this study examined Sal-B for in vivo therapeutic reversal of established emphysema in two rat models. Emphysema was induced with porcine pancreatic elastase (PPE) and cigarette smoke extract (CSE), and established by day 21. Sal-B was then spray-dosed to the lung three times weekly for three weeks. Functional treadmill exercise endurance; morphological airspace enlargement and alveolar destruction; apoptosis, cell proliferation and tissue matrix proteins; phosphorylated STAT3 (pSTAT3) and VEGF expressions; neutrophil accumulation; and lipid peroxidation were determined. In both models, Sal-B at 0.2 mg/kg significantly reversed impaired exercise endurance by 80 and 64%; airspace enlargement [mean linear intercept (MLI)] by 56 and 67%; and alveolar destructive index (%DI) by 63 and 66%, respectively. Induced apoptosis activity [cleaved caspase-3] was normalized by 94 and 82%; and cell proliferation activity [proliferative cell nuclear antigen (PCNA)] was stimulated by 1.6 and 2.1-fold. In the PPE-induced model, Sal-B reduced induction of lung's matrix metalloproteinase (MMP)-9 and MMP-2 activities by 59 and 94%, respectively, and restored pSTAT3 and VEGF expressions to the healthy lung levels, while leaving neutrophil accumulation unchecked [myeloperoxidase (MPO) activity]. In the CSE-induced model, Sal-B elevated pSTAT3 and VEGF expressions both by 1.8-fold over the healthy lung levels, and normalized induced lipid peroxidation [malondialdehyde (MDA) activity] by 68%. These results provide an in vivo proof-of-concept for Sal-B as one of the first anti-emphysema agents enabling reversal of alveolar structural destruction and loss via local lung treatment by virtue of its STAT3 activation and VEGF stimulation.

Raised VEGF: High sensitivity and specificity in the diagnosis of POEMS syndrome.

ObjectiveTo investigate the sensitivity and the specificity of serum vascular endothelial growth factor (sVEGF) for the diagnosis of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome in patients with a neuropathy (NP) and to identify confounding causes of raised vascular endothelial growth factor (VEGF) in this context to improve accuracy.MethodsWe studied the specificity and sensitivity of sVEGF for the diagnosis of POEMS syndrome in a cohort of 195 consecutive patients with an NP in serum samples from June 2009 to November 2013, including 27 untreated patients with POEMS syndrome. We then studied VEGF in other neuropathies and analyzed causes of elevated VEGF in a multiple logistic regression analysis in a larger cohort of 236 patients including 168 with a non-POEMS NP and 68 without NP.ResultsThe sensitivity of elevated sVEGF for the diagnosis of POEMS was 100%. Its specificity was 91% in patients with an NP and 92% in patients with an NP and a paraproteinemia. sVEGF was much higher in POEMS before treatment. sVEGF was not significantly elevated in any non-POEMS NP or hematologic disease group. Multiple logistic regression showed that anemia with low iron was a significant predictor for elevated sVEGF and that chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea-hypopnoea syndrome were significant predictors for very elevated sVEGF.InterpretationWe confirmed the high sensitivity and specificity of an elevated VEGF for the diagnosis of POEMS. However, VEGF testing should be repeated, particularly after acute illnesses. Raised sVEGF should be interpreted with caution unless anemias with low iron, sleep apnea, COPD, cancers, vasculitis, and chronic inflammatory diseases are excluded.Classification of evidenceThis study provides class IV evidence that elevated sVEGF levels accurately identifies patients with POEMS syndrome.

The relationship of serum VEGF and sVEGFR-1 levels with vascular involvement in patients with Behçet's disease

Behçet’s disease (BD) is a rare, chronic, inflammatory disorder characterized by multisystemic vasculitis including mucocutaneous, neurologic, and ophthalmic involvement. Our aim is to compare vascular endothelial growth factor (VEGF) and soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) levels in BD, among the patients having or not having organ involvement, disease activation and especially vascular involvement. Fifty-five patients with BD, 25 of which were accompanied by vascular involvement, and 31 control subjects were included in the study. Disease activity was assessed with the Turkish version of Behçet Disease Current Activity Form (BDCAF) and active vasculitis lesions at the time of study were recorded. Age at diagnosis was 32.2 ± 4.6, while the mean duration of BD was 96.3 (72.3) months. The median for BDCAF score was 2.0 (range 0, 3.0), and 29 (52%) of patients had active BD. The serum VEGF and sVEGFR-1 levels in patients with BD were significantly higher than that in controls [(298 (338.5) pg/mL; 93 (93.5) pg/mL in patients and 136.2 (73) pg/mL; 56.5 (48.5) pg/mL in controls, respectively, p < .001 for both values] while difference in VEGF/sVEGFR-1 ratio was obtained close to borderline of significance (p = .03). Our study is the first report indicating elevated serum VEGF, sVEGFR-1, and more importantly VEGF/sVEGFR-1 ratio could play an important role in the development of trombosis in BD. VEGF and/or sVEGFR-1 should not be evaluated independently in the same patient group and the ratio of these two parameters is a more important indicator, especially in the evaluation of BD especially with vascular involvement together with the duration of disease.

Vascular endothelial growth factor and pulmonary hypertension in children with beta thalassemia major

ObjectiveThe purpose of this study was to illustrate the association between vascular endothelial growth factor level and pulmonary artery hypertension in children with β-thalassemia major. MethodThis case–control study was conducted on 116 children with β-thalassemia major; 58 of them had pulmonary artery hypertension. They were compared to 58 healthy children who were age and sex-matched (control group). Serum levels of vascular endothelial growth factor and echocardiographic assessment were done for all children. ResultsVascular endothelial growth factor serum level was significantly higher in children with β-thalassemia major with pulmonary artery hypertension than in those without pulmonary artery hypertension, as well as in control groups (p<0.001). Vascular endothelial growth factor serum level had a significant positive correlation with pulmonary artery pressure and serum ferritin, as well as a significant negative correlation with the duration of chelation therapy. Logistic regression analysis revealed that elevated vascular endothelial growth factor (Odd Ratio=1.5; 95% Confidence Interval, 1.137–2.065; p=0.005) was an independent risk factor of pulmonary artery hypertension in such children. Vascular endothelial growth factor serum level at a cutoff point of >169pg/mL had 93.1% sensitivity and 93.1% specificity for the presence of pulmonary artery hypertension in children with β-thalassemia major. ConclusionElevated vascular endothelial growth factor serum level is associated with pulmonary artery hypertension in children with β-thalassemia.

Cinnamaldehyde accelerates wound healing by promoting angiogenesis via up-regulation of PI3K and MAPK signaling pathways

The bark of Cinnamomum cassia (C. cassia) has been used for the management of coronary heart disease (CHD) and diabetes mellitus. C. cassia may target the vasculature, as it stimulates angiogenesis, promotes blood circulation and wound healing. However, the active components and working mechanisms of C. cassia are not fully elucidated. The Shexiang Baoxin pill (SBP), which consists of seven medicinal materials, including C. cassia etc., is widely used as a traditional Chinese patent medicine for the treatment of CHD. Here, 22 single effective components of SBP were evaluated against the human umbilical vein endothelial cells (HUVECs). We demonstrated that in HUVECs, cinnamaldehyde (CA) stimulated proliferation, migration, and tube formation. CA also activated the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Furthermore, the secretion of vascular endothelial growth factor (VEGF) from HUVECs was increased by CA. In vivo, CA partially restored intersegmental vessels in zebrafish pretreated with PTK787, which is a selective inhibitor for vascular endothelial growth factor receptor (VEGFR). CA also showed pro-angiogenic efficacy in the Matrigel plug assay. Additionally, CA attenuated wound sizes in a cutaneous wound model, and elevated VEGF protein and CD31-positive vascular density at the margin of these wounds. These results illustrate that CA accelerates wound healing by inducing angiogenesis in the wound area. The potential mechanism involves activation of the PI3K/AKT and MAPK signaling pathways. Such a small non-peptide molecule may have clinical applications for promoting therapeutic angiogenesis in chronic diabetic wounds and myocardial infarction.

Serum cytokine responses in Rickettsia felis infected febrile children, Ghana

The intracellular pathogen Rickettsia felis causes flea-borne spotted fever and is increasingly recognized as an emerging cause of febrile illness in Africa, where co-infection with Plasmodium falciparum is common. Rickettsiae invade endothelial cells. Little is known, however, about the early immune responses to infection. In this study, we characterize for the first time the cytokine profile in the acute phase of illness caused by R. felis infection, as well as in plasmodial co-infection, using serum from 23 febrile children < 15 years of age and 20 age-matched healthy controls from Ghana. Levels of IL-8 (interleukin-8), IP-10 (interferon-γ-induced protein-10), MCP-1 (monocyte chemotactic protein-1), MIP-1α (macrophage inflammatory protein-1α) and VEGF (vascular endothelial growth factor) were significantly elevated in R. felis mono-infection; however, IL-8 and VEGF elevation was not observed in plasmodial co-infections. These results have important implications in understanding the early immune responses to R. felis and suggest a complex interplay in co-infections.

Atypical central retinal artery occlusion as the first presentation of POEMS syndrome: a case report

BackgroundPOEMS syndrome is a plasma cell disorder, which clinically manifests from paraneoplastic syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. The most common ocular manifestation is optic disc swelling, whereas other ocular manifestations; cystoid macular edema, serous macular detachment, venous sinus thrombosis, infiltrative orbitopathy, uveitis, neovascularization of the disc, peripapillary choroidal neovascularization and optic disc drusen, had also been reported.Case presentationA 52-year-old Thai man presented with 5-day sudden painless visual loss in the left eye. Ocular examination revealed visual acuity of 20/20 and no light perception in the right and left eye, respectively. Right fundoscopic examination was significant for hyperemic generalized optic disc swelling. Left fundoscopic examination revealed opaque and edematous entire retina giving the appearance of central retinal artery occlusion (CRAO) along with pallid “chalky white” optic disc swelling. Fluorescein angiography showed profound leakage of bilateral optic nerve heads and arteriolar filling defect in macular area along with leakage of small retinal arterioles in the left eye. Indocyanine green angiography demonstrated choroidal filling defect in the left eye only. Neuroimaging showed enhancement and luminal narrowing of left internal carotid artery, early subacute watershed infarctions in the left cerebral hemisphere and pachymeningeal enhancement. Cerebrospinal fluid analysis revealed high protein level with normal opening pressure. Intravenous methylprednisolone was initially started without any benefit. After extensive investigations, diagnosis of “POEMS syndrome” was made based on polyneuropathy, elevated lambda light chain level, elevated plasma vascular endothelial growth factor (VEGF), hepatomegaly, spinal sclerotic bone lesions, and thrombocytosis. Furthermore, sural nerve biopsy demonstrated neuropathy and positive VEGF staining. He was treated with eight cycles of bortezomib, cyclophosphamide and dexamethasone (BorCyDex). Polyneuropathy and thrombocytosis had remarkably improved after 2nd cycle, whereas, visual impairment had shown no recovery. Hepatomegaly was significantly reduced after the completion of BorCyDex. Our case eventually received autologous hematopoietic stem cell transplantation with high dose melphalan.ConclusionsTo our knowledge, we illustrated the first patient given CRAO as the first presentation and ocular finding ever reported in POEMS syndrome. Both cerebral and ocular infarctions were presumably the result of VEGF-induced cranial vasculopathy as evidenced by neuroimaging.

Severity-Related Increase and Cognitive Correlates of Serum VEGF Levels in Alzheimer's Disease ApoE4 Carriers.

Vascular endothelial growth factor (VEGF) is an angioneurin involved in the regulation of vascular and neural functions relevant for the pathophysiology of Alzheimer's disease (AD), but the influence of AD severity and ApoE4 status on circulating VEGF and its relationship with cognition has not been investigated. We assessed serum VEGF levels and cognitive performance in AD, amnestic mild cognitive impairment (MCI), and control subjects. VEGF levels were higher in AD patients than in MCI cases and controls (p < 0.05) and showed a progressive increase with clinical severity in the whole study population (p < 0.01). Among AD patients, severity-related VEGF elevations were significant in ApoE4 carriers (p < 0.05), but not in non-carriers. Increased VEGF levels were associated with disease severity and showed mild correlations with cognitive impairment that were only consistent for the ADAS-cog+ items remembering test instructions (memory) and maze task (executive functions) in the group of AD patients (p < 0.05). On the other hand, higher VEGF values were related to better memory and language performance in ApoE4 carriers with moderately-severe AD. According to these results showing severity- and ApoE4-related differences in serum VEGF and its cognitive correlates, it is suggested that increases in VEGF levels might represent an endogenous response driven by pathological factors and could entail cognitive benefits in AD patients, particularly in ApoE4 carriers. Our findings support the notion that VEGF constitutes a relevant molecular target to be further explored in AD pathology and therapy.

Elevated serum vascular endothelial growth factor in treatment-resistant schizophrenia treated with electroconvulsive therapy: Positive association with therapeutic effects

Objectives: As the name implies, vascular endothelial growth factor (VEGF) enhances angiogenesis, promotes vascular permeability, and stimulates neurogenesis in the adult brain. Furthermore, animal model studies have shown that electroconvulsive therapy (ECT), which is primarily utilised in cases of treatment-resistant schizophrenia (TRS), regulates the expression of VEGF. The current study focuses largely on the effect of ECT on VEGF serum concentration, and the relationship between VEGF and therapeutic effects in patients diagnosed with TRS.Methods: Participants comprised 40 TRS patients and 43 healthy controls. Clinical severity was assessed (i.e. 1 day before commencement of ECT and 1 day following ECT) using the positive and negative syndrome scale (PANSS). Blood samples were also collected for VEGF measurements at corresponding time points.Results: Pre-treatment serum VEGF levels were significantly lower in TRS patients compared to healthy controls. VEGF concentrations increased significantly following ECT, whereas no difference was found in controls. Moreover, there was a positive correlation between the change in VEGF and therapeutic effects.Conclusions: Elevated serum VEGF in TRS treated with ECT is positively associated with therapeutic effects, suggesting that alterations in VEGF levels may constitute an index by which to evaluate the improvement in clinical condition.

Tracheal aspirate VEGF and sphingolipid metabolites in the preterm infant with later development of bronchopulmonary dysplasia.

Vascular endothelial growth factor (VEGF) and sphingolipid metabolites, sphingosine 1-phosphate (S1P), and ceramides are important to lung development and repair. We hypothesized specific sphingolipid and VEGF alterations would be associated with BPD development and aimed to investigate the early tracheal aspirate (TA) VEGF and S1P relationship with later diagnosis of preterm infant bronchopulmonary dysplasia, BPD. TA VEGF and lipidomics were measured in TA from Infants <32 weeks gestational age at birth with and without later BPD. BPD was defined using the NICHD severity BPD definition. Clinical demographics and medical course were identified with statistical analysis performed with JMP, Statistical Analysis Software. The analysis included 25 infants (9 NoBPD and 16 BPD) with mean gestational age of 27.8 ± 2.5 SD weeks and 25.1 ± 1.9 SD weeks respectively, P < 0.01. Later development of BPD was associated with elevated mean TA VEGF 604.3 ± 150.2 SE pg/mL versus NoBPD 120 ± 34.3 SE pg/mL, elevated S1P, 11.5 ± 2.3 SE pmol/mL versus NoBPD 4.8 ± 0.6 SE pmol/mL, and elevated selected ceramides during the first week of life. Airway VEGF and sphingolipid metabolites were distinctly elevated within the first days of postnatal life in preterm infants with later BPD progression. These biomarkers may be useful as indicators of lung injury development or as targets to decrease BPD risk.