Enhancement Of Vascular Permeability Research Articles

Analysis of circulating vascular endothelial growth factor and its soluble receptors in patients with different forms of chronic urticaria.

Background. Vascular endothelial growth factor (VEGF) is a powerful enhancer of vascular permeability and inflammatory response; however its significance in chronic urticaria is poorly recognised. Aim. To compare free circulating levels of VEGF and its soluble receptors (sVEGFR1 and VEGFR2) in patients with different forms of chronic urticaria. Methods. The concentrations of VEGF and its receptors in plateletpoor plasma (PPP)/plasma were measured using enzyme-linked immunosorbent assay in chronic urticaria: (1) chronic spontaneous urticaria (CSU) with positive autologous serum skin test (ASST), (2) CSU with negative response to ASST, (3) CSU with concomitant euthyroid Hashimoto's thyroiditis (CSU/Hashimoto), (4) delayed pressure urticaria (DPU), and the healthy subjects. Results. There were no significant differences in VEGF concentration in PPP between CSU groups and the healthy subjects. Contrary, VEGF concentration was significantly higher in DPU and CSU/Hashimoto patients as compared with the healthy subjects and CSU groups. Furthermore, VEGF value in CSU/Hashimoto patients during the remission was similar to that of the active period and significantly higher than the healthy subjects; VEGF concentration was significantly correlated with TSH. Plasma concentrations of sVEGF1 and sVEGF2 were similar in chronic urticaria patients and the healthy subjects. Conclusions. Increased free circulating VEGF concentration may result from the urticarial process itself as well as concomitant Hashimoto's thyroiditis.

A Standardized Traditional Chinese Medicine Preparation Named Yejuhua Capsule Ameliorates Lipopolysaccharide-Induced Acute Lung Injury in Mice via Downregulating Toll-Like Receptor 4/Nuclear Factor-κB.

A standardized traditional Chinese medicine preparation named Yejuhua capsule (YJH) has been clinically used in treatments of various acute respiratory system diseases with high efficacy and low toxicity. In this study, we were aiming to evaluate potential effects and to elucidate underlying mechanisms of YJH against lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice. Moreover, the chemical analysis and chromatographic fingerprint study were performed for quality evaluation and control of this drug. ALI was induced by intratracheal instillation of LPS (5 mg/kg) into the lung in mice and dexamethasone (5 mg/kg, p.o.) was used as a positive control drug. Results demonstrated that pretreatments with YJH (85, 170, and 340 mg/kg, p.o.) effectively abated LPS-induced histopathologic changes, attenuated the vascular permeability enhancement and edema, inhibited inflammatory cells migrations and protein leakages, suppressed the ability of myeloperoxidase, declined proinflammatory cytokines productions, and downregulated activations of nuclear factor-κB (NF-κB) and expressions of toll-like receptor 4 (TLR4). This study demonstrated that YJH exerted potential protective effects against LPS-induced ALI in mice and supported that YJH was a potential therapeutic drug for ALI in clinic. And its mechanisms were at least partially associated with downregulations of TLR4/NF-κB pathways.

Discovery of a novel vascular endothelial growth factor (VEGF) with no affinity to heparin in Gloydius tsushimaensis venom

Strong vascular permeability enhancing activity was found only in the venom of Gloydius tsushimaensis, in Tsushima island, Japan, when examined together with the venoms of G. blomhoffii snakes in several areas of Japan and of G. ussuriensis in South Korea. The active protein purified by using Superdex 75 and Mono Q columns showed no affinity to heparin, and migrated on SDS-PAGE with molecular weights of 26 and 13 kDa under nonreducing and reducing conditions, respectively, showing that it exists as homodimer. Its N-terminal amino acid sequence was highly homologous to those of snake venom vascular endothelial growth factors (VEGFs). The sequence of this protein, named GtVF, was inferred from the one base-substituted two cDNAs (438 bp) obtained via the 3′ RACE. The phylogenetic analysis suggested the presence of a new type of snake venom VEGFs including GtVF with no affinity to heparin in addition to the known three types of snake venom VEGFs with high affinity to heparin. Since the vascular permeability enhancement by GtVF was inhibited by the antibody against kinase insert domain-containing receptor (KDR), the vascular permeability enhancing activity of GtVF arises through KDR but without heparin binding.

Quantitative observation of focused-ultrasound-induced vascular leakage and deformation via fluorescein angiography and optical coherence tomography

Focused ultrasound (FUS) is a recently discovered noninvasive technique for local and temporal enhancement of vascular permeability, which facilitates drug delivery from the vessels into the surrounding tissue. However, exposure to FUS at a high intensity may cause permanent damage. To investigate the effects of the FUS treatment on blood vessels, we propose to use fluorescein angiography (FA) and optical coherence tomography (OCT) for real-time observation of the diffusion of fluorescence dye from blood vessels and to evaluate the morphological changes of the vessels in vivo. With time-resolved FA imaging, the relationship between the exposed power and the improved permeability of the vessels can be assessed according to the enhancement of the fluorescent intensity due to the dye leakage. Furthermore, the variation of the time-resolved fluorescent intensities can be used to identify the occurrence of dye leakage. In contrast, OCT can be implemented for the reconstruction of tissue microstructures. To quantitatively evaluate the morphological changes of the vessels after the FUS exposure with OCT, a new algorithm was proposed to estimate the vessel area based on the comparison of backscattering properties resulting from the tissue and vascular structures. Results showed that the vessel area increased as the exposed power increased, and the area became significantly larger at a higher FUS exposure power of 10 W. In conclusion, integrated FA and OCT observation can be potentially effective for monitoring the outcome and investigating the effects of FUS treatment.

Vitronectin increases vascular permeability by promoting VE-cadherin internalization at cell junctions.

BackgroundCross-talk between integrins and cadherins regulates cell function. We tested the hypothesis that vitronectin (VN), a multi-functional adhesion molecule present in the extracellular matrix and plasma, regulates vascular permeability via effects on VE-cadherin, a critical regulator of endothelial cell (EC) adhesion.Methodology/Principal FindingsAddition of multimeric VN (mult VN) significantly increased VE-cadherin internalization in human umbilical vein EC (HUVEC) monolayers. This effect was blocked by the anti-αVβ3 antibody, pharmacological inhibition and knockdown of Src kinase. In contrast to mult VN, monomeric VN did not trigger VE-cadherin internalization. In a modified Miles assay, VN deficiency impaired vascular endothelial growth factor-induced permeability. Furthermore, ischemia-induced enhancement of vascular permeability, expressed as the ratio of FITC-dextran leakage from the circulation into the ischemic and non-ischemic hindlimb muscle, was significantly greater in the WT mice than in the Vn −/− mice. Similarly, ischemia-mediated macrophage infiltration was significantly reduced in the Vn −/− mice vs. the WT controls. We evaluated changes in the multimerization of VN in ischemic tissue in a mouse hindlimb ischemia model. VN plays a previously unrecognized role in regulating endothelial permeability via conformational- and integrin-dependent effects on VE-cadherin trafficking.Conclusion/SignificanceThese results have important implications for the regulation of endothelial function and angiogenesis by VN under normal and pathological conditions.

Antivascular endothelial growth factor agents for neovascular age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of severe visual loss and blindness over the age of 50 in developed countries. Vascular endothelial growth factor (VEGF) is considered as a critical molecule in the pathogenesis of choroidal neovascularization (CNV), which characterizes the neovascular AMD. Anti-VEGF agents are considered the most promising way of effectively inhibition of the neovascular AMD process. VEGF is a heparin-binding glycoprotein with potent angiogenic, mitogenic and vascular permeability-enhancing activities specific for endothelial cells. Two anti-VEGF agents have been approved by the US Food and Drug Administration (FDA) for the treatment of neovascular AMD. Pegaptanib sodium, which is an aptamer and ranibizumab, which is a monoclonal antibody fragment. Another humanized monoclonal antibody is currently off-label used, bevacizumab. This paper aims to discuss in details the effectiveness, the efficacy and safety of these three anti-VEGF agents. New anti-VEGF compounds which are recently investigated for their clinical usage (VEGF-trap, small interfering RNA) are also discussed for their promising outcomes.

High-Dose Antiangiogenic Therapy for Glioblastoma: Less May Be More?

Targeting angiogenesis in glioblastoma rapidly reduces vascular permeability and contrast enhancement on MRI and prolongs progression-free survival. The long-term efficacy of bevacizumab and other antiangiogenic agents is limited, however, because of the rapid development of resistance. Alternative dosing approaches may be one mechanism of prolonging therapeutic efficacy.

Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial proliferation, arterial relaxation, vascular permeability and angiogenesis by dobesilate

Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and vascular permeability which is associated with many pathological processes. 2,5-hydroxybenzene sulfonate (DHBS; dobesilate) is a small molecule with anti-angiogenic activity that has been described as an inhibitor of fibroblast growth factors (FGF). The aim of the present study was to evaluate the effects of DHBS on VEGF-induced actions. The effects of DHBS were evaluated on VEGF-induced proliferation in human umbilical vein endothelial cells (HUVEC) and rat aorta relaxation, as well as on in vivo VEGF-induced skin vascular permeability and neovascularization in rats. DHBS at 50 and 100 μM concentration significantly inhibited the proliferation of HUVEC induced by VEGF (10 ng/ml), without significantly affecting HUVEC proliferation in the absence of VEGF. Rapid VEGF-induced activation of Akt in HUVEC was also prevented by DHBS (100 μM). Additionally, DHBS (2 μM) specifically inhibited the relaxation of rat aorta induced by VEGF (0.1 to 30 ng/ml), but not endothelium-dependent relaxation to acetylcholine (1 nM to 10 μM). The in vivo enhancement of vascular permeability caused by VEGF injection (50 μl at 10 ng/ml) in rat skin was also inhibited by DHBS co-administration (200 μM) (74.8 ± 3.8% inhibition of dye extravasation). Administration of DHBS (200 mg/kg/day; i.p.) also reduced VEGF-induced angiogenesis in vivo. DHBS inhibits main responses elicited in vitro and in vivo by VEGF. As a dual antagonist of VEGF and FGF activities, DHBS could be of therapeutic interest in the treatment of diseases related to VEGF/FGF overproduction and excessive angiogenesis.

Receptor for advanced glycation end-products-mediated inflammation and diabetic vascular complications.

Receptor for advanced glycation end-products-mediated inflammation and diabetic vascular complications.

FLAIR, T1 contrast enhancement, MR perfusion, and FDG PET following hypofractionated stereotactic radiotherapy (HFSRT), bevacizumab (BEV), and temozolomide (TMZ) for glioblastoma (GBM).

2048 Background: In GBM, VEGF inhibition decreases vascular permeability and MRI contrast enhancement (CE), which may or may not reflect meaningful anti-tumor activity. We sought to evaluate the relationships between different imaging modalities and anti-tumor activity in a prospective phase II trial of BEV, TMZ and HFSRT in GBM. Methods: Newly diagnosed GBM pts (N=40) received HFSRT with concomitant/ adjuvant BEV and TMZ. All pts underwent dynamic susceptibility contrast MR perfusion (DSC) at baseline, after HFSRT and every 2m. An FDG-PET scan was done at cycle 6. McDonald and RANO response criteria were applied. Results: DSC showed early/progressive decreases in relative cerebral blood volume (rCBV): baseline mean rCBV: 2.77; 6 weeks: 1.65 (p=0.014); 2m: 1.07 (p<0.001); 4m: 0.98 (p<0.001). Conversely, the extent of FLAIR hypersignal progressively increased (mean diameter product: 953, 1165, 1145, 1384 at 6 wks, 2m, 4m and 6m). Response rates per McDonald vs RANO were: complete response (27 vs 10%), partial (63 vs 63%), stable disease (3% vs 20%), progression (7 vs 7%). Because progressive FLAIR occurred within the RT port, time to radiographic progression per McDonald and RANO were identical: median 13m. Residual hypermetabolism seen at the 6m PET (N=6/31) predicted poor survival (p<0.001). Three pts with progressive FLAIR but not CE underwent re-resection; two had true PD and one had mainly radionecrosis. Conclusions: As treatment failure was mostly local, RANO criteria did not shorten time to progression compared to McDonald. DSC depicted early changes in rCBV linked to VEGF modulation, validating DSC as a reliable tool to evaluate anti-VEGF properties of new drugs in vivo. However, VEGF modulation was not predictive of durable anti-tumor activity. A positive PET at 6m predicted poor survival, indicating treatment failure even if other imaging modalities suggested otherwise. However, tumor progression may still be present despite negative PET and DSC, particularly in the setting of increasing non-enhancing FLAIR within the RT port. New imaging tools and improved response criteria are needed to guide management of these pts.

ANTI-infective Therapeutics from the Lepidopteran Model Host Galleria mellonella

The larvae of the greater wax moth Galleria mellonella prosper in use both as surrogate alternative model hosts for human pathogens and as a whole-animal-high-throughput-system for in vivo testing of antibiotics or mutant-libraries of pathogens. In addition, a broad spectrum of antimicrobial peptides and proteins has been identified in this insect during past decade among which some appear to be specific for Lepidoptera. Its arsenal of immunity-related effector molecules encompasses peptides and proteins exhibiting potent activity against bacteria, fungi or both, whose potential as new anti-infective therapeutics are presently being explored. Of particular interest is the insect metalloproteinase inhibitor (IMPI) which has been discovered in G. mellonella. The IMPI exhibits a specific and potent activity against thermolysin-like microbial metalloproteinases including a number of prominent virulence and/or pathogenic factors of human pathogens which are responsible for severe symptoms such as septicemia, hemorrhagic tissue bleeding, necrosis and enhancement of vascular permeability. The IMPI and antimicrobial peptides from G. mellonella may provide promising templates for the rational design of new drugs since evidence is available that the combination of antibiotics with inhibitors of pathogen-associated proteolytic enzymes yields synergistic therapeutic effects. The potential and limitations of insect-derived gene-encoded antimicrobial compounds as anti-infective therapeutics are discussed.

Anti-VEGF Compounds in the Treatment of Neovascular Age Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness among elderly patients in developed countries. Although the pathogenesis of AMD is still largely unknown, it is now well known that vascular endothelial growth factor (VEGF) plays a pivotal role in the growth of the abnormal blood vessels (i.e. choroidal neovascularization, CNV) which characterizes the "wet form" of this ocular disease. Therefore, inhibiting VEGF has turned out to be a good way of more effectively controlling neovascular AMD. VEGF is a heparin-binding glycoprotein with potent angiogenic, mitogenic and vascular permeability-enhancing activities specific for endothelial cells. Currently two anti-VEGF compounds have been approved by the US Food and Drug Administration (FDA) for the treatment of neovascular AMD: pegaptanib and ranibizumab. Off-label usage of bevacizumab, an anti-VEGF agent similar to ranibizumab, has also become fairly common. The substantial improvement of visual acuity noticed in patients treated with ranibizumab has made this drug the gold standard for AMD therapy. However, as with many new therapies, there are unresolved issues, including safety, cost, and dosing frequency. This review describes in details the properties and efficacy of the three anti-VEGF agents in use in clinical practice. Promising emerging anti-VEGF strategies (VEGF-trap, small interfering RNA, tyrosine kinase inhibitors) which aim to improve outcomes, safety and treatment burden through novel mechanisms of action are also discussed.

Bradykinin and the Pathogenesis of Hereditary Angioedema

Bradykinin and the Pathogenesis of Hereditary Angioedema

LOX-1 mediates vascular lipid retention under hypertensive state

Hypertension is a powerful independent risk factor for atherosclerotic cardiovascular diseases; however, the precise molecular mechanisms whereby hypertension promotes atherosclerotic formation remain to be determined. The interaction between oxidized low-density lipoprotein (oxLDL) and its receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays a critical role in atherogenesis. To clarify how hypertension promotes atherosclerosis, we investigated specific roles of LOX-1 in acceleration of lipid deposition under a hypertensive state. We employed a model of stroke-prone spontaneously hypertensive rats (SHR-SP) that exhibits acute lipid deposition in mesenteric artery induced by high fat and salt loading. These vascular lipid deposition lesions share similar characteristics with the initial lesions of human atherosclerosis. The enhanced LOX-1 expression in SHR-SP was associated with oxidized LDL deposited in vascular wall. Anti-LOX-1 neutralizing antibody dramatically suppressed the lipid deposition in vivo in SHR-SP. Vitamin E decreased serum oxLDL-like LOX-1 ligands, and suppressed the vascular lipid deposition. The vascular permeability, evaluated by the leakage of Evans blue, was markedly enhanced by pretreatment of oxLDL. The enhancement of vascular permeability induced by oxLDL was suppressed by anti-LOX-1 antibody. The enhanced expression and activation of LOX-1 mediated the enhancement of vascular permeability, which contributed to the vascular lipid accumulation under hypertensive states.

Effects of resveratrol on expression of vascular endothelial growth factor in human gingival fibroblasts stimulated by periodontal pathogens

Objective. To investigate the effects of resveratrol, a naturally occurring polyphenol, on the expression of vascular endothelial growth factor (VEGF) in human gingival fibroblast culture in response to vesicles and outer membrane proteins from periodontopathic bacteria. Material and methods. Human gingival fibroblasts were stimulated with vesicles and outer membrane proteins from Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. In human gingival fibroblast cultures treated with or without resveratrol, VEGF production was evaluated by means of enzyme-linked immunosorbent assay and VEGF mRNA expression by means of reverse transcription polymerase chain reaction analysis. Vascular permeability enhancement was measured by the leakage of intravenously injected dye at the injection site of supernatant from cultures of human gingival fibroblasts stimulated by vesicles and outer membrane proteins. Results. Resveratrol significantly inhibited the increased production of VEGF by human gingival fibroblasts in response to vesicles and outer membrane proteins from periodontopathic bacteria, as shown by the detection of these proteins and their mRNA in vitro. Moreover, resveratrol treatment significantly decreased vascular permeability enhancement induced by supernatant from human gingival fibroblast cultures stimulated by vesicles and outer membrane proteins. Conclusions. Overall, these findings suggest that resveratrol inhibits production of VEGF by stimulated human gingival fibroblasts and can inhibit vascular permeability, suggesting a therapeutic role for it in pathogenic bacteria-induced periodontal inflammation.

Safety of Bevacizumab in Advanced Ovarian and Müllerian Cancers: A Review

Abstract Despite the armamentarium of cytotoxic agents available in the treatment of patients with advanced recurrent ovarian, fallopian, and peritoneal disease, enthusiasm for these agents has been tempered by their toxicity profile, poor response rate, and eventually, the emergence of resistance. In recent years, focus has shifted to an understanding of signaling pathways that promote angiogenesis. Tumor angiogenesis is well established as essential for the growth and metastasis of solid tumors. This process involves the recruitment of mature vasculature and circulating endothelial cells and proangiogenic soluble mediators, one of which includes the vascular endothelial growth factor (VEGF). This factor has several known activities, such as mitogenesis, angiogenesis, endothelial survival, enhancement of vascular permeability, and effects on hemodynamic status. Vascular endothelial growth factor is a 45-kDA glycoprotein that is regulated by oxygen tension and also by various growth factors, hormones, and oncogenes. Inhibiting VEGF and its action has been the focus of intense research in several disciplines and has emerged as an attractive focus for the design of targeted therapeutics in the field of ovarian cancer. Numerous agents targeting angiogenesis are currently being explored. These include monoclonal antibodies to the VEGF ligand, small tyrosine kinase inhibitors that target the vascular endothelial receptor, and soluble decoy VEGF receptors. The most studied agent to date has been bevacizumab, a recombinant humanized monoclonal antibody to the VEGF ligand. Although the efficacy of this agent has been well established in multiple disciplines, several concerns have been raised as to the unique adverse effects of this agent.

Involvement of Human Leukocyte Antigen Class II Antibody in Pathogenesis of Transfusion-Related Acute Lung Injury (TRALI): Vascular Permeability Enhancement

Involvement of Human Leukocyte Antigen Class II Antibody in Pathogenesis of Transfusion-Related Acute Lung Injury (TRALI): Vascular Permeability Enhancement

Involvement of Human Leukocyte Antigen Class II Antibody in Pathogenesis of Transfusion-Related Acute Lung Injury (TRALI): Vascular Permeability Enhancement

Vascular endothelial cells regulate the passage of fluids, solutes, and cells from the vascular space to the tis- sues. Disruption of vascular integrity is involved in the pathogenesis of inflammatory diseases including transfusion- related acute lung injury (TRALI), a most severe nonhemolytic transfusion reaction with symptoms such as dyspnea and/or hypotension and fever. Pulmonary edema, due to increased vascular permeability for macromolecules and plasma, is a hallmark of TRALI. The mortality rate of TRALI ranges from 5 to 10%. While donor antibodies (Abs) against human leukocyte antigen (HLA) class I and granulocytes are regarded as causative factors, various clinical studies have demon- strated the roles of anti-HLA class II-Ab on the etiology of TRALI, although the detailed mechanisms have not been clari- fied. Over several years we have investigated to clarify the underlying mechanism by which anti-HLA class II Abs cause an increase in endothelial permeability. In this review, we show that anti-HLA class II Ab generates proinflammatory cy- tokines and chemokines from HLA class II positive mononuclear cells of peripheral blood in an Fc R-dependent manner. As a result, the produced interleukin-1 and tumor necrosis factor- lead to increased endothelial permeability via the nu- clear factor- B pathway but not apoptosis of endothelial cells. These findings provide a better understanding of the roles of anti-HLA class II Ab in the etiology of TRALI.

Enhanced interstitial flow as a contributing factor in neointima formation: (shear) stressing vascular wall cell types other than the endothelium

AS BLOOD FLOWS THROUGH the vascular network, it creates fluid mechanical forces that can be predicted based on established physical principles of fluid dynamics. The major components of flow-generated force in the vasculature include pressure and shear stress, both of which are imparted directly onto the vessel wall. The realization that different patterns (laminar vs. oscillatory), magnitudes (high vs. low), and spatial gradients of shear stress can influence the overall vessel homeostasis has led to an intense investigation into how shear stress regulates the structural and functional phenotype of the blood vessel. Through the work of many dedicated laboratories, we are now certain that shear stress exerts a profound effect on endothelial cells which line all vessels. The endothelium, in turn, can communicate the condition of the hemodynamic environment to which it is exposed to underlying vascular components such as smooth muscle and adventitial fibroblasts, resulting in a propagation of shear stress effects to the entire vessel wall. To illustrate this point, changes in shear stress are perceived by the endothelium and converted in biochemical signals, which are then relayed to enzyme systems that generate vasoactive substances such as nitric oxide (NO). Through a paracrine effect, NO activates the molecular machinery that governs smooth muscle contractility, thereby translating changes in shear stress into an alteration of vessel diameter. In the normal, intact vasculature, the endothelial layer forms an interface between the blood and the remaining components of the vascular wall. Thus vascular smooth muscle and adventitial fibroblasts are remote from the actual hemodynamic shear forces. As a result, the direct influence of shear stress on these mural cell types has received little attention. Rather, the stretch generated via the rhythmic expansion and contraction of the vessel wall with each successive pulse of pressure and bloodflow appears to be the dominant hemodynamic stimuli for smooth muscle and, potentially, adventitial cells. Indeed, cyclic stretch has been shown to activate mechanotransduction pathways that lead to functional responses in these cell, and readers are directed to an excellent review in this area (4). So, if smooth muscle and adventitial cells are shielded, in a relative sense, from shear stress and are most responsive to hemodynamic-imposed stretch, the influences of shear stress would seem to be of little concern in these cell types. However, if one considers the forces produced by the flow of interstitial fluid through the vessel wall, then shear stress forces may in fact be an important factor in regulating smooth muscle cells and vessel wall integrity. This concept may have clinical ramifications given that factors which enhance interstitial flow (i.e., chemical or mechanical injury to the endothelium and inflammation and hypertension induced enhancement of vascular permeability) are associated with vessel remodeling and neointima formation. The basic notion that vascular smooth muscle and fibroblasts are responsive to shear stress has been tested by several investigative teams in the past. Laminar shear stress ranging from 10 to

Relationship Between Serum Vascular Endothelial Growth Factor and Airway Hyperresponsiveness in Asthmatic Children

RATIONALE: Bronchial asthma is physiologically characterized by variable airflow obstruction and airway hyperresponsiveness (AHR). Vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis and enhancer of vascular permeability with subsequent edema and thereby contributes to the pathogenesis of asthma. The aim of the present study was to investigate a relationship between serum VEGF levels and methacholine AHR in asthmatic children.