Vascular Endothelial Growth factor-A Concentrations Research Articles

Lidocaine effects on neutrophil extracellular trapping and angiogenesis biomarkers in postoperative breast cancer patients with different anesthesia methods: a prospective, randomized trial

BackgroundAnesthesia techniques and drug selection may influence tumor recurrence and metastasis. Neutrophil extracellular trapping (NETosis), an immunological process, has been linked to an increased susceptibility to metastasis in individuals with tumors. Furthermore, recurrence may be associated with vascular endothelial growth factor A (VEGF-A), a mediator of angiogenesis. This study investigates the impact of lidocaine (combined with sevoflurane or propofol anesthesia ) during breast cancer surgery inhibits the expression of biomarkers associated with metastasis and recurrence (specifically H3Cit, NE, MPO, MMP-9 and VEGF-A).MethodsWe randomly assigned 120 women undergoing primary or invasive breast tumor resection to receive one of four anesthetics: sevoflurane (S), sevoflurane plus i.v. lidocaine (SL), propofol (P), and propofol plus i.v. lidocaine (PL). Blood samples were collected before induction and 3 h after the operation. Biomarkers associated with NETosis (citrullinated histone H3 [H3Cit], myeloperoxidase [MPO], and neutrophil elastase [NE]) and angiogenesis were quantified using enzyme-linked immunosorbent assays.ResultsPatient and breast tumor characteristics, along with perioperative management, did not differ between study groups. In intra-group comparisons, S and P groups demonstrated a statistically significant increase in post-operative MPO (S group: 10.39[6.89–17.22] vs. 14.31[8.55–20.87] ng ml-1, P = 0.032; P group: 9.45[6.73–17.37] vs. 14.34[9.87–19.75] ng ml-1, P = 0.035)and NE(S group: 182.70[85.66-285.85] vs. 226.20[91.85-391.65] ng ml-1, P = 0.045; P group: 154.22[97.31–325.30] vs. 308.66[132.36-483.57] ng ml-1, P = 0.037) concentrations compared to pre-operative measurements, whereas SL and PL groups did not display a similar increase. H3Cit, MMP-9, and VEGF-A concentrations were not significantly influenced by the anesthesia techniques and drugs.ConclusionsRegardless of the specific technique employed for general anesthesia, there was no increase in the postoperative serum concentrations of MPO and NE after perioperative lidocaine infusion compared to preoperative serum concentrations. This supports the hypothesis that intravenous lidocaine during cancer surgery aimed at achieving a cure may potentially decrease the likelihood of recurrence. Further interpretation and discussion of clinical implications are warranted, emphasizing the significance of these findings in the context of cancer surgery and recurrence prevention.Clinical trial registrationChiCTR2300068563.

VEGFA, VEGFR1, VEGFR2 serum and cerebrospinal fluid concentration in patients with acute leukemia

Background. Vascular endothelial growth factor A (VEGFA) is one of the most important factors for regulation of hematopoietic stem cells differentiation. It is involved in leukemogenesis and central nervous system (CNS) damage in acute leukemia. According to the literature, the VEGFA production by blast cells is increased, but the values of serum concentration and the associations with CNS involvement are contradictory.Aim. evaluate the VEGFA, VEGFR1, VEGFR2 concentration in serum and cerebrospinal fluid of patient with different types of acute leukemia in disease onset and during treatment.Materials and methods. The concentration of VEGFA in serum and cerebrospinal fluid was studied in 74 primary patients with acute leukemia. The comparison group consisted of 67 healthy donors. VEGFR1, VEGFR2 were studied in serum and cerebrospinal fluid in 34 patients at the onset of the disease. The comparison group consisted of 10 healthy donors. For the analysis, an enzyme immunoassay was used on a semi-automatic Personal Lab analyzer (Adaltis) and Affymetrix eBioscience human VEGF-A Platinum ELISA reagents.Results. Serum VEGFA concentration was statistically significantly lower in acute leukemia patients than that of donors (median 149.78 and 432.19 pg/ml respectively; p <0.0001). Factor deficiency was significantly more pronounced in patients with blastemia (p <0.015). During antitumor therapy, there was a tendency to increase the amount of the factor in the blood serum. Serum concentration of soluble VEGFR2 was also lower in patients than that of donors (6949.9 and 8795.9 pg/ml respectively; p = 0.0026). For concentration of VEGFR1 such deviations were not found. The concentrations of VEGFR1 and VEGFR2 in serum were higher than in cerebrospinal fluid (p <0.0001), while VEGFR1 showed a positive correlation between serum and cerebrospinal fluid concentrations. the concentration of VEGFR1 in the cerebrospinal fluid was significantly lower in patients with B-lymphoblastic leukemia/lymphoma compared to other types of leukemia.Conclusion. the concentration of VEGFA in serum decreases in patients with blastemia, this may indicate a lack of secretion and excessive consumption of the factor by blast cells with a decrease in the proportion of leukocytes that normally secrete the factor. In the cerebrospinal fluid, the concentrations of VEGFR1 and VEGFR2 are lower than in serum, with the lowest values being found in patients with B-lymphoblastic leukemia/lymphoma, but no relationship with the development of CNS involvement was found.

The Inhibitory Effect of NSAIDs and Opioids on Spinal Fusion: An animal model.

Translational Research. To evaluate the relative effects of NSAIDs, opioids, and a combination of the two on spinal fusion inhibition in a rodent model. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are common postoperative analgesic agents. Since NSAIDs inhibit the cyclooxygenase (COX) pathway they are seldom prescribed following spinal fusion. Opioids may be given instead, but recent evidence suggests opioids also adversely affect spinal fusion quality and success. Eighty male Sprague-Dawley rats underwent L4-5 posterior lumbar fusion and were given one of the following analgesia regimens: saline, morphine (6mg/kg), ketorolac (4mg/kg), or morphine (3mg/kg) and ketorolac (2mg/kg). Serum samples were drawn to evaluate systemic pro-osteoblastic cytokines and vascular endothelial growth factor-A (VEGF-A) levels, which were measured via enzyme-linked immunosorbent assays (ELISA). After six weeks, the rats were sacrificed and the operated spinal segments underwent manual palpation, microCT, and histological analysis. Manual palpation scores were significantly diminished in the opioid, NSAID, and multimodal groups when compared to control (P<0.001). MicroCT fusion scores (P<0.001) and fusion rates (control: 75% vs. NSAID: 35% vs. opioid: 0% vs. combination: 15%, P<0.001) were significantly diminished in the treatment groups. The bone volume (BV) to tissue volume (TV) ratio (BV/TV) (P<0.001) and bone mineral density (BMD) (P<0.001) were all lower in the treatment groups with the opioid and combined groups having the lowest BMD. Although statistically insignificant (P<0.09), the concentration of VEGF-A was greater in the control group compared to opioids, NSAIDs, and the combined group. Opioids and NSAIDs, both independently and combined, inhibited spinal fusion and caused inferior bony callus. Administration of opioids resulted in the lowest rate of spinal fusion. We propose this may be due to the inhibition of VEGF-A, which limits angiogenesis to the burgeoning fusion mass.

Production of angiogenesis mediators and the structure of the vascular wall in the heart in ischemic cardiomyopathy

Background. In the pathogenesis of ischemic cardiomyopathy (ICMP), angiopoiesis remains unexplored.The aim. To describe the vasculature of the heart and the imbalance of angiogenesis mediators in the coronary circulation in association with the number of endothelial progenitor cells (EPC) and desquamated endothelial cells (DEC) in the blood of patients with coronary heart disease (CHD), suffering and not suffering from ICMP.Methods. Fifty-two patients with CHD (30 patients with ICMP, 22 patients without ICMP), 15 healthy donors were examined. The content of EPC (CD14+CD34+VEGFR2+) in the blood from the cubital vein and DEC (CD45–CD146+) in the blood from the coronary sinus and the cubital vein was determined by flow cytometry. The concentrations of VEGF-A (vascular endothelial growth factor A), PDGF (platelet-derived growth factor), and SDF-1 (stromal cell-derived factor 1) in blood plasma were recorded using immunofluorescence assay; the angiopoietin-2, MMP-9 (matrix metallopeptidase 9) were recorded using enzyme immunoassay. In myocardial biopsies the specific area of vessels and the expression of αSMA (smooth muscle alpha-actin) were determined by morphometric and immunohistochemical methods.Results. In the peripheral blood of patients with CHD, regardless of the presence of ICMP, the DEC content exceeded the physiological level, and the VEGF-A, PDGF, angiopoietin-2, and MMP-9 corresponded to the norm. In CHD patients without cardiomyopathy, there was an excess of SDF-1 and EPC in the blood from the cubital vein, and in ICMP, their physiological significance was noted. In the coronary blood flow in patients with CHD without cardiomyopathy, an increase in the concentration of PDGF was found, which was not determined in patients with ICMP, who had an increased content of DEC, angiopoietin-2 and MMP-9. The specific area of the vessels in the patients of the two groups was comparable; the expression of αSMA in ICMP was 6.2 times lower than in patients with CHD without cardiomyopathy.Conclusion. The development of ICMP is accompanied by impaired maturation of vessels in the myocardium, associated with the absence of a compensatory reaction of activation of cellular and humoral factors of angiogenesis.

Associations of Angiopoietin 2 and Vascular Endothelial Growth Factor-A Concentrations with Clinical End Points.

Angiopoietin 2 regulates endothelial function partially mediated by vascular endothelial growth factor-A (VEGF-A) and may play a role in diabetic kidney disease (DKD). We assessed the association of angiopoietin 2 and VEGF-A with cardiorenal outcomes and investigated the effect of canagliflozin on angiopoietin 2 and VEGF-A concentrations. Two thousand five hundred sixty-five study participants with DKD and available plasma samples treated with canagliflozin or placebo in the Canagliflozin and Kidney Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial were included. Angiopoietin 2 and VEGF-A concentrations were measured at baseline, year 1, and year 3. The primary composite end point of the trial was a composite of kidney failure, doubling of the serum creatinine level, and kidney or cardiovascular death. Patients with the highest baseline quartile of angiopoietin 2, but not VEGF-A, concentration had the highest risk clinical profile. Treatment with canagliflozin significantly lowered concentrations of angiopoietin 2 (adjusted geometric mean ratio: 0.94; 95% confidence interval, 0.92 to 0.95; P < 0.001), but not VEGF-A. In multivariable-adjusted modeling, each 50% increment in log baseline angiopoietin 2 concentrations was associated with a higher risk of primary composite outcome (hazard ratio, 1.27; 95% confidence interval, 1.13 to 1.43). Angiopoietin 2 change at year 1 compared with baseline explained 10% of the effect of canagliflozin on the primary composite outcome. VEGF-A concentrations were not associated with outcomes, alone or in combination with angiopoietin 2. Higher angiopoietin 2 levels were associated with cardiorenal risk among individuals with DKD independent of VEGF-A. Canagliflozin lowered angiopoietin 2 concentrations. Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy, NCT02065791 .

Long-Term Effects of Suramin on Renal Function in Streptozotocin-Induced Diabetes in Rats.

In short-term diabetes (3 weeks), suramin, a drug used clinically, affects renal function and the expression of vascular endothelial growth factor A (VEGF-A), which may be involved in the pathogenesis of diabetic nephropathy, the main cause of end-stage renal disease. In the present study, we evaluated the long-term (11 weeks) effects of suramin (10 mg/kg, i.p., once-weekly) in diabetic rats. Concentrations of VEGF-A, albumin, soluble adhesive molecules (sICAM-1, sVCAM-1), nucleosomes, and thrombin-antithrombin complex (TAT) were measured by ELISA, total protein was measured using a biuret reagent. Glomerular expression of VEGF-A was evaluated by Western blot, mRNA for VEGF-A receptors in the renal cortex by RT-PCR. The vasoreactivity of the interlobar arteries to acetylcholine was assessed by wire myography. Long-term diabetes led to an increased concentration of VEGF-A, TAT, and urinary excretion of total protein and albumin, and a decrease in the concentration of sVCAM-1. We have shown that suramin in diabetes reduces total urinary protein excretion and restores the relaxing properties of acetylcholine relaxation properties to non-diabetic levels. Suramin had no effect on glomerular expression VEGF-A expression and specific receptors, and on sICAM-1 and nucleosomes concentrations in diabetic rats. In conclusion, the long-term effect of suramin on the kidneys in diabetes, expressed in the reduction of proteinuria and the restoration of endothelium-dependent relaxation of the renal arteries, can be considered as potentially contributing to the reduction/slowing down of the development of diabetic nephropathy.

Neurofilament light chain in plasma as a sensitive diagnostic biomarker of peripheral neurotoxicity: In Vivo mouse studies with oxaliplatin and paclitaxel - NeuroDeRisk project

Identifying compounds that are neurotoxic either toward the central or the peripheral nervous systems (CNS or PNS) would greatly benefit early stages of drug development by derisking liabilities and selecting safe compounds. Unfortunately, so far assays mostly rely on histopathology findings often identified after repeated-dose toxicity studies in animals. The European NeuroDeRisk project aimed to provide comprehensive tools to identify compounds likely inducing neurotoxicity. As part of this project, the present work aimed to identify diagnostic non-invasive biomarkers of PNS toxicity in mice. We used two neurotoxic drugs in vivo to correlate functional, histopathological and biological findings. CD1 male mice received repeated injections of oxaliplatin or paclitaxel followed by an assessment of drug exposure in CNS/PNS tissues. Functional signs of PNS toxicity were assessed using electronic von Frey and cold paw immersion tests (oxaliplatin), and functional observational battery, rotarod and cold plate tests (paclitaxel). Plasma concentrations of neurofilament light chain (NF-L) and vascular endothelial growth factor A (VEGF-A) were measured, and histopathological evaluations were performed on a comprehensive list of CNS and PNS tissues. Functional PNS toxicity was observed only in oxaliplatin-treated mice. Histopathological findings were observed dose-dependently only in paclitaxel groups. While no changes of VEGF-A concentrations was recorded, NF-L concentrations were increased only in paclitaxel-treated animals as early as 7 days after the onset of drug administration. These results show that plasma NF-L changes correlated with microscopic changes in the PNS, thus strongly suggesting that NF-L could be a sensitive and specific biomarker of PNS toxicity in mice.

Monitoring vascular endothelial growth factor-a levels during follow-up after hematopoietic stem cell transplantation in pediatric patients at a Mexican hospital: A pilot study

Vascular endothelial growth factors are proteins that participate in processes related to normal physiology, solid tumors and hematologic malignancies; however, their role in hematopoietic stem cell transplantation (HSCT) requires further investigation. To better define the role and changes in vascular endothelial growth factor-A (VEGF-A) in the context of HSCT, we conducted an observational prospective analysis of VEGF-A expression during the early period after HSCT in pediatric patients. Thirty-seven pediatric patients who underwent hematopoietic stem cell transplantation at the Federico Gómez Children's Hospital in Mexico between June 2016 and July 2018 were prospectively enrolled in this study. Ribonucleic acid was isolated from the venous blood of these patents on Days 0, +7, +14, +21, +28, and +35 after transplantation, and TaqMan reverse transcription-polymerase chain reaction was performed using specific primers and a probe for VEGF-A. The concentration of VEGF-A was determined using a complementary deoxyribonucleic acid control. Data were analyzed using one-way ANOVA and Dunnett post hoc tests. Statistical analysis was performed using SPSS version 25. There were significant differences in the concentrations of VEGF-A between Day 0 vs. Day +28 (p = 0.009 95% CI=0.02–0.24), Day 0 vs. Day +35 (p = 0.006; 95% CI=0.03–0.28) and Day 7 vs. Day + 35 (p = 0.006; 95% CI=0.03–0.24) after allogeneic HSCT. We observed significant increases in the VEGF-A concentration during the early period after stem cell transplantation in pediatric patients. Our results provide important insights that should be considered a basis for future clinical trials of pediatric HSCT, including the monitoring of VEGF-A concentrations, proteins and in vitro analysis.

PREGNANT WOMEN WITH COVID-19 AND PLACENTA ANGIOGENESIS

Aim of our research was to conduct a clinical and laboratory analysis of the impact of COVID-19 on pregnancy and the condition of the fetus. Materials and Methods: At the first stage, we conducted a retrospective examination of 50 pregnant women treated at Ternopil Municipal Hospital No.2 (Ukraine) between November 2020 and January 2022 with the history of COVID-19, confirmed by PCR test, and 25 pregnant COVID-19 negative pregnant women (control group). At the second stage, we performed prospective cohort study and involved 40 pregnant women treated with the history of COVID-19, confirmed by PCR, and 10 pregnant COVID-19 negative women with a physiological course of pregnancy as a control group.Women were divided into the following groups: group I -10 women diagnosed with COVID-19 during the first trimester of pregnancy: group II-15 women diagnosed during the second trimester; group III-15 women diagnosed during the third trimester. Ultrasound examination and cardiotocograms were performed to assess fetus status. Blood samples were collected at delivery. To determine whether COVID-19 could alter placental angiogenesis, vascular endothelial growth factor A (VEGFA), PlGF and interleuin-32-α were assessed. Results: We identified that concentration of VEGFA was 95.30±5.65 pg/ml in control group. In women who had COVID-19 in first trimester, this index was 1.3 times higher, in second trimester 1.63 times higher and in third trimester by 2 times compared to control group. PlGF concentration was only 27,4 percent in group I, 16 percent in group II and 30 percent in group III,compared to control group. Concentration of interleuin-32-α was 67.27±5.63 pg/ml in control group and increased to 167 percent in group I, by 2.8 times in group II and by 6.3 times in group III compared to control group. Conclusions: COVID-19 has a negative impact on placental angiogenesis, including VEGFA and PlGF. Fetal post-COVID-19 syndrome requires timely diagnosis of disorders and further study. Post-COVID-19 syndrome is an immune-dependent pathology in which the processes of protracted cytokine activation occur in the body of a pregnant woman.

VEGF gene polymorphism in complicated infective endocarditis

Introduction. Infective endocarditis (IE) is a bacterial disease with frequent pathogen localization on the heart valve apparatus. IE is characterized by rapid development of heart failure and frequent thromboembolic complications (TEC). IE features are accounted for by foreign pathogen nature and state of human immune system (IS). The imbalanced IS in infective endocarditis is manifested by impaired cytokine-mediated interactions. This confirms the rationality of studying cytokines to advance understanding of the pathogenesis for various conditions. Most cytokine genes are characterized by polymorphism and existing isoforms underlying disease predisposition. Genetic polymorphism of vascular endothelial growth factor A (VEGF-A) plays an important role in the induction of vasculogenesis and angiogenesis. The pathogenetic VEGF role in IE has not been thoroughly studied. Research objective analysis of polymorphic nucleotide sequence variants in the vascular endothelial growth factor gene, taking into account a relation with its serum concentration in patients with infective endocarditis. Materials and methods. 86 patients treated with verified diagnosis of infective endocarditis at the Scientific Research Institute Regional Clinical Hospital No. 1 of Krasnodar were divided into two clinical groups in accordance with the IE course: Group 1 IE with TEC (n = 44), group 2 IE without TEC (n = 42), and the control group consisted of 20 apparently healthy individuals. The concentration of serum VEGF-A (pg/mL) was measured by ELISA on day 1 of hospitalization. Genomic DNA was isolated from whole blood leukocytes and used to determine the frequency of genotypes of VEGF gene polymorphic variants. Results. Significant differences in the frequency distribution of VEGF-rs2010963 genotypes between patients with infective endocarditis and control group were revealed: G/G (OR = 0.25; p = 0.012) and G/C (OR = 4.28; p = 0.022), as well as differences between VEGF concentrations for various SNP-rs2010963 genotypes (p = 0.0001). A study of VEGF genotype frequency distribution between patients of clinical groups showed a significantly decreased frequency of the genotype G/G (rs2010963) in the IE group with TEC (OR = 0.21; p = 0.014) and increased frequency of G/C (OR = 4.72; p = 0.024) compared with the control group, whereas in patients with IE without TEC, significant (p = 0.0003) differences in serum concentrations of VEGF-rs2010963 were found in accordance with genotypes GG/CC (p = 0.01) and GG/GC (p = 0.003). Conclusion. The relationship between the VEGF genotypes (G/G and G/C of rs2010963 polymorphism) and related serum concentration among patients with IE was revealed. Carriers of the minor C allele (rs2010963) had higher serum VEGF levels. The results obtained complement and systematize current scientific data on the disease pathogenesis, as well as focus on the genetic determinant of the developing complications.

Evaluation of VEGF-A and CCL2 in dogs with brachycephalic obstructive airway syndrome or canine idiopathic pulmonary fibrosis and in normocephalic dogs

Brachycephalic obstructive airway syndrome (BOAS) and canine idiopathic pulmonary fibrosis (CIPF) of West Highland White Terriers (WHWTs) often cause intermittent or chronic hypoxemia. Our objective was to evaluate serum and bronchoalveolar lavage fluid (BALF) concentrations of hypoxemia-related proinflammatory mediators vascular endothelial growth factor A (VEGF-A) and chemokine (CC motif) ligand 2 (CCL2) in brachycephalic dogs (BDs) and WHWTs with and without CIPF. Additionally, effects of BOAS severity and ageing on these mediators were assessed.114 BDs (28 English Bulldogs (EBs), 37 French Bulldogs, 49 Pugs), 16 WHWTs with CIPF, 26 healthy WHWTs, and 39 normocephalic control dogs were included. Fifty-four BDs were re-examined after two to three years. Bead-based immunoassay was used for proinflammatory mediator measurements.Compared with controls, significantly higher serum concentrations of VEGF-A were seen in EBs (P = 0.009) and of CCL2 in CIPF and healthy WHWTs (P < 0.001; P = 0.002). BALF samples were available from controls, EBs, and WHWTs. VEGF-A was significantly lower in EBs (P < 0.001) and in CIPF and healthy WHWTs (P = 0.006; P = 0.007) and CCL2 was higher in CIPF WHWTs (P = 0.01) compared with controls. Between visits, only serum VEGF-A significantly decreased in BDs (P < 0.001), but breed, BOAS severity, or its change had no significant effect.In conclusion, in EBs with BOAS proinflammatory changes in VEGF-A were detected in both serum and BALF. Ageing reduced serum VEGF-A in BDs. In WHWTs, our results confirmed earlier findings of CCL2 as an important biomarker for CIPF.

Serum vascular endothelial growth factor is associated with cardiovascular involvement and response to therapy in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare histiocytosis, considered to be an inflammatory myeloid neoplasm. Tropism for specific involvements of the disease remains unexplained. Vascular endothelial growth factor-A (VEGF) is implicated in cancer pathophysiology and mutations of the RAS oncogene have been shown to induce upregulation of VEGF gene expression. We therefore hypothesized that VEGF might play a particular role in ECD pathophysiology. We conducted a retrospective, single-center study to assess serum VEGF (sVEGF) concentrations and determine whether they were associated with the characteristics of ECD patients, and to determine whether VEGF was expressed by histiocytes. We evaluated 247 ECD patients, 53.4% of whom had sVEGF levels above the normal range (>500 pg/mL). Patients with high sVEGF levels more frequently had cardiac and vascular involvement (58.3% vs. 41.4%, P=0.008 and 70.5% vs. 48.3%, P=0.0004, respectively). In treatment-naïve patients (n=135), the association of C-reactive protein >5 mg/L and sVEGF >500 pg/mL was strongly associated with vascular involvement (odds ratio=5.54 [95% confidence interval: 2.39-13.62], P<0.001), and independently associated with cardiac involvement (odds ratio=3.18 [95% confidence interval: 1.34-7.83], P=0.010) after adjustment for the presence of the BRAF V600E mutation. Changes in sVEGF concentration on treatment were associated with a response of cardiac involvement on consecutive cardiac magnetic resonance images. All histological samples analyzed (n=24) displayed histiocytes with intracytoplasmic expression of VEGF, which was moderate to high in more than 90% of cases. Our study suggests a role for VEGF in cardiac and vascular involvement in ECD.

The blunted vascular endothelial growth factor-A (VEGF-A) response to high-altitude hypoxia and genetic variants in the promoter region of the VEGFA gene in Sherpa highlanders.

BackgroundSherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, which may be achieved by mechanisms promoting microcirculatory blood flow and capillary density at high altitudes for restoring oxygen supply to tissues. Vascular endothelial growth factors (VEGFs) are important signaling proteins involved in vasculogenesis and angiogenesis which are stimulated by hypoxia. We hypothesize that the VEGF-A, the major member of the VEGF family, and the gene encoding VEGF-A (VEGFA) play a part in the adaptation to high-altitude hypoxia in Sherpa highlanders.MethodsFifty-one Sherpa highlanders in Namche Bazaar village at a high altitude of 3,440 meters (m) above sea level and 76 non-Sherpa lowlanders in Kathmandu city at 1,300 m in Nepal were recruited for the study. Venous blood was sampled to obtain plasma and extract DNA from each subject. The plasma VEGF-A concentrations were measured and five single-nucleotide polymorphisms (SNPs, rs699947, rs833061, rs1570360, rs2010963, and rs3025039) in the VEGFA were genotyped. The VEGF-A levels and allelic frequencies of the SNPs were compared between the two populations.ResultsA significant difference in oxygen saturation (SpO2) was observed between the two ethnic groups locating at different elevations (93.7 ± 0.2% in Sherpas at 3,440 m vs. 96.7 ± 0.2% in non-Sherpas at 1,300 m, P < 0.05). The plasma VEGF-A concentration in the Sherpas at high altitude was on the same level as that in the non-Sherpas at low altitude (262.8 ± 17.9 pg/ml vs. 266.8 ± 21.8 pg/ml, P = 0.88). This result suggested that the plasma VEGF-A concentration in Sherpa highlanders was stable despite a high-altitude hypoxic stimulus and that therefore the Sherpas exhibited a phenotype of blunted response to hypoxic stress. Moreover, the allele frequencies of the SNPs rs699947, rs833061, and rs2010963 in the promoter region of the VEGFA were different between the Sherpa highlanders and non-Sherpa lowlanders (corrected P values = 3.30 ×10−5, 4.95 ×10−4, and 1.19 ×10−7, respectively).ConclusionsSherpa highlanders exhibited a blunted VEGF-A response to hypoxia at high altitudes, which was speculated to be associated with the distinctive genetic variations of the SNPs and haplotype in the promoter region of VEGFA in Sherpa highlanders.

Decreased plasma levels of PDGF-BB, VEGF-A, and HIF-2α in preterm infants after ibuprofen treatment.

IntroductionIbuprofen is one of the most common non-steroidal anti-inflammatory drugs used to close patent ductus arteriosus (PDA) in preterm infants. PDA is associated with bronchopulmonary dysplasia (BPD), while PDA closure by ibuprofen did not reduce the incidence of BPD or death. Previous studies have indicated an anti-angiogenesis effect of ibuprofen. This study investigated the change of angiogenic factors after ibuprofen treatment in preterm infants.MethodsPreterm infants with hemodynamically significant PDA (hsPDA) were included. After confirmed hsPDA by color doppler ultrasonography within 1 week after birth, infants received oral ibuprofen for three continuous days. Paired plasma before and after the ibuprofen treatment was collected and measured by ELISA to determine the concentrations of platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor A (VEGF-A), and hypoxia-inducible factor-2α (HIF-2α).Results17 paired plasma from infants with hsPDA were collected. The concentration of PDGF-BB and VEGF-A significantly decreased after ibuprofen treatment (1,908 vs. 442 pg/mL for PDGF-BB, 379 vs. 174 pg/mL for VEGF-A). HIF-2α level showed a tendency to decrease after ibuprofen treatment, although the reduction was not statistically significant (p = 0.077).ConclusionThis study demonstrated decreased vascular growth factors after ibuprofen exposure in hsPDA infants.

A Shorter-Bout of HIIT Is More Effective to Promote Serum BDNF and VEGF-A Levels and Improve Cognitive Function in Healthy Young Men.

Objective: The aim of this study was to investigate the effects of single bouts of high-intensity interval training (HIIT) with different duration on serum brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor-A (VEGF-A) levels and cognitive function in healthy young men. Methods: Twelve healthy young men were participated in two HIIT treatments (20 min HIIT and 30 min HIIT) in a random order. BDNF, VEGF-A, cortisol, testosterone, blood lactic acid were measured and cognitive function was assessed by Stroop test (CWST) and Digital Span test (DST) before, immediately after, and 30 min after HIIT. Results: 20 and 30 min HIIT increased BLa (both p < 0.01), cortisol (20 min HIIT: p < 0.05; 30 min HIIT: p < 0.01), and testosterone (both p < 0.05) levels immediately when compared with their baselines. While BLa and cortisol were significantly higher in 30 min HIIT group than in 20 min HIIT group. Moreover, BDNF concentration (p < 0.01), DST-F (p < 0.01) and DST-B (p < 0.05) were increased and response time of Stroop was decreased immediately after HIIT only in 20 min HIIT group. VEGF-A concentration was increased immediately after HIIT in both groups (p < 0.01), but after 30 min recovery, it was returned to the baseline in the 20 min HIIT group and was lower than the baseline in 30 min HIIT group (p < 0.05). Conclusion: Twenty minutes HIIT is more effective than 30 minutes HIIT for promoting serum levels of BDNF and VEGF-A as well as cognitive function in healthy young men.

Vascular Endothelial Growth Factor as a Potential Biomarker of Neuroinflammation and Frontal Cognitive Impairment in Patients with Alcohol Use Disorder.

(1) Background: Alcohol Use Disorder (AUD) is associated with functional disruption of several brain structures that may trigger cognitive dysfunction. One of the mechanisms of alcohol-associated cognitive impairment has been proposed to arise from its direct impact on the immune system, which culminates in the release of cytokines and chemokines which can eventually reach the brain. Alcohol can also disrupt the blood–brain barrier, facilitating the penetration of pro-inflammatory molecules throughout vascular endothelial growth factor A (VEGFA). Thus, alcohol-induced alterations in chemokines and VEGFA might contribute to the neuroinflammation and cognitive impairment associated with AUD. (2) Methods: The present cross-sectional study investigates whether patients with AUD (n = 86) present cognitive disability associated to alterations in plasma concentration of SDF-1, fractalkine, eotaxin, MCP-1, MIP-1α and VEGFA when compared to control subjects (n = 51). (3) Results: The analysis indicated that SDF-1 and MCP-1 concentrations were higher in AUD patients than in controls. Concentrations of VEGFA were higher in AUD patients with severe frontal deficits, and the score of frontal lobe functions was negatively correlated with VEGFA and fractalkine. Acute alcohol effects on VEGFA plasma levels in healthy volunteers demonstrated the induction of VEGFA release by heavy alcohol drinking. VEGFA was positively correlated with pro-inflammatory chemokines in AUD patients with frontal cognitive impairment. (4) Conclusions: we propose VEGFA/chemokine monitoring as biomarkers of potential cognitive impairment in AUD patients.

Co-Detection of VEGF-A and Its Regulator, microRNA-181a, May Indicate Central Nervous System Involvement in Pediatric Leukemia.

Central nervous system (CNS) involvement is a leading cause of therapy-refractory pediatric acute lymphoblastic leukemia (pALL), which is aggravated by underdiagnosing CNS disease with the currently used cell-based approach of cerebrospinal fluid (CSF) diagnostics. Our study focused on developing novel subcellular CNS leukemia indicators in the CSF and the bone marrow (BM) of patients with pALL. Serial liquid biopsy samples (n = 65) were analyzed by Elisas to measure the level of essential proteins associated with blast cell CNS trafficking, vascular endothelial growth factor A (VEGF-A) and integrin alpha 6 (ITGA6). In CSF samples from early induction chemotherapy, VEGF-A concentration were uniformly elevated in the CNS-positive group compared to those patients without unambiguous meningeal infiltration (9 vs Nine patients, Δc = 17.2 pg/ml, p = 0.016). Expression of miR-181a, a VEGFA-regulating microRNA which showed increased level in CNS leukemia in our previous experiments, was then paralleled with VEGF-A concentration. A slight correlation between the levels of miR-181a and VEGF-A indicators in CSF and BM samples was revealed (n = 46, Pearson’s r = 0.36, p = 0.015). After validating in international cohorts, the joint quantification of miR-181a and VEGF-A might provide a novel tool to precisely diagnose CNS involvement and adjust CNS-directed therapy in pALL.

Vascular endothelial growth factor-A level in human breast milk after intravitreal injection of ranibizumab: a case report

BackgroundRanibizumab is one of intravitreal anti-vascular endothelial growth factor agents. It is applied in the treatments of choroidal neovascularization, age-related macular degeneration, diabetic macular edema, and macular edema secondary to retinal vein occlusion. Preliminary evidence suggests that intravitreal ranibizumab may enter the plasma and human breast milk in very low-level concentration. As a precaution, breastfeeding is not recommended during the treatment of intravitreal injection of ranibizumab. There are limited data regarding the change of anti-vascular endothelial growth factor concentration in human breast milk after intravitreal injection of ranibizumab, especially in the first 24 h after injection. The purpose of this report is to analyse the concentration change of vascular endothelial growth factor-A in human breast milk with time, in the short term after intravitreal injection of ranibizumab.Case presentationIn June 2018, a 30-year-old patient breastfeeding a six-month-old baby was diagnosed with choroidal neovascularization of left eye in Eye Hospital of Wenzhou Medical University. She received four administrations of 0.5 mg intravitreal injection of ranibizumab of the left eye, and breast milk was collected just before the injection, and 1–3, 6, 12, 24, 48, and 72 h after intravitreal injection, and assessed for vascular endothelial growth factor-A concentration. The change in vascular endothelial growth factor-A concentration in human breast milk showed the same trend after each injection, decreasing significantly within 6–12 h (about 20–30% lower), and increasing to pre-injection level by 24 h after injection.ConclusionsThe concentration of vascular endothelial growth factor-A in human breast milk of a mother who continues lactating dropped initially and rose to pre-injection level about 24 h after intravitreal injection of ranibizumab. The data may offer more information to evaluate the impact of anti-vascular endothelial growth factor agent intravitreal injection of lactating mothers and their breastfed infants.

Assessment of the Concentration of Endogenous Factors Regulating Angiogenesis, VASH-1 and VEGF-A, in the Blood Serum of Patients with Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NENs) constitute about 2% of all malignant neoplasms, and the angiogenesis process in these tumors is still of a great interest. Vasohibin-1 (VASH-1) is an angiogenesis inhibitor, while vascular endothelial growth factor A (VEGF-A) is one of the main factors promoting vascular formation. The subject of this study was to assess serum concentration of these factors in patients with diagnosed NEN and in control group. Methods. The study group consisted of 120 patients with diagnosed NENs, while the control group consisted of 69 healthy volunteers. The concentrations of VASH-1 and VEGF-A in serum were tested using the ELISA. We also analyzed the association of the concentration of these factors with demographic data (e.g., age and gender), body mass index (BMI), primary tumor location, histological grade, metastasis, clinical staging, selected biochemical parameters and markers of NENs, and information on smoking habits. Results. The mean concentration of VASH-1 was 218.8 ± 359.8 pg/ml in the study group and 973.1 ± 1239.4 pg/ml in the control group, that difference was statistically significant (p < 0.05). In the NEN group, the highest concentration of VASH-1 was in patients with pancreatic NENs in relation to NENs with different location of the primary tumor (p < 0.05). Negative correlation was found between the concentration of VASH-1 and serotonin (rS = −0.19, p < 0.05). No statistically significant differences were observed for VEGF-A (p = 0.658). Conclusions. Patients with NENs showed lower serum level of VASH-1 in comparison to healthy volunteers. The highest level of VASH-1 was observed in tumors localized in pancreas. This might reflect the relevant function of VASH-1 in NENs and requires further evaluation to further knowledge of angiogenesis in NENs. Furthermore, the serum concentration of VEGF-A showed no statistical differences and probably does not have diagnostic value in this group of patients.

Expression of vascular endothelial growth factor A (VEGFA), placental growth factor (PlGF) and insulin-like growth factor 1 (IGF-1) in serum from women undergoing frozen embryo transfer

VEGFA, PlGF and IGF-1 are three main angiogenic factors which play significant roles in embryo implantation. However, the relationship between serum expressions of VEGFA, PlGF and IGF-1 and pregnancy outcomes has not been fully illustrated. In this study, serum specimens were collected precisely on day 7 after the LH surge in a natural non-conception cycle from 38 infertile patients who underwent frozen embryo transfer (FET) treatment. ELISA was used to determine the concentrations of VEGFA, PlGF and IGF-1. Serum levels of VEGFA, PlGF and IGF-1 were compared between patients who conceived (n=25) and who did not (n=13). Correlation and linear regression analyses were used to investigate the correlations of serum angiogenic factors and β-hCG MoM levels in the pregnant group. The results demonstrated that no significant difference was found in serum VEGFA, PlGF or IGF-1 concentration between pregnant and non-pregnant women. Spearman correlation analysis revealed a positive correlation between IGF-1 concentration and β-hCG level in pregnant participants (rs = 0.490, p = 0.013). In conclusion, serum IGF-1 level correlated positively with β-hCG level in pregnant women, which may provide information on the prognostic value of IGF-1 in this group of women.