Enhanced bronchial expression of vascular endothelial growth factor and receptors (Flk-1 and Flt-1) in patients with chronic obstructive pulmonary disease.

Ongoing inflammatory processes resulting in airway and vascular remodelling characterise chronic obstructive pulmonary disease (COPD). Vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) could play a role in tissue remodelling and angiogenesis in COPD. The cellular expression pattern of VEGF, Flt-1, and KDR/Flk-1 was examined by immunohistochemistry in central and peripheral lung tissues obtained from ex-smokers with COPD (forced expiratory volume in 1 second (FEV(1)) <75% predicted; n = 14) or without COPD (FEV(1) >85% predicted; n = 14). The immunohistochemical staining of each molecule was quantified using a visual scoring method with grades ranging from 0 (no) to 3 (intense). VEGF, Flt-1, and KDR/Flk-1 immunostaining was localised in vascular and airway smooth muscle (VSM and ASM) cells, bronchial, bronchiolar and alveolar epithelium, and macrophages. Pulmonary endothelial cells expressed Flt-1 and KDR/Flk-1 abundantly but not VEGF. Bronchial VEGF expression was higher in microvascular VSM cells and ASM cells of patients with COPD than in patients without COPD (1.7 and 1.6-fold, p<0.01, respectively). VEGF expression in intimal and medial VSM (1.7 and 1.3-fold, p<0.05) of peripheral pulmonary arteries associated with the bronchiolar airways was more intense in COPD, as was VEGF expression in the small pulmonary vessels in the alveolar region (1.5 and 1.7-fold, p<0.02). In patients with COPD, KDR/Flk-1 expression was enhanced in endothelial cells and in intimal and medial VSM (1.3, 1.9 and 1.5-fold, p<0.02) while endothelial Flt-1 expression was 1.7 times higher (p<0.03). VEGF expression was significantly increased in bronchiolar and alveolar epithelium as well as in bronchiolar macrophages (1.5-fold, p<0.001). The expression of VEGF in bronchial VSM and mucosal microvessels as well as bronchiolar epithelium was inversely correlated with FEV(1) (r<-0.45; p<0.01). VEGF and its receptors Flt-1 and KDR/Flk-1 may be involved in peripheral vascular and airway remodelling processes in an autocrine and/or paracrine manner. This system may also be associated with epithelial cell viability during airway wall remodelling in COPD.

Kranenburg AR ，de Boer WI ，Alagappan VK ，Sterk PJ ，Sharma HS ... -  《-》

Gene expression of vascular endothelial growth factor and its receptors and angiogenesis in bronchial asthma.

Angiogenesis is a feature of airway remodeling in bronchial asthma. The mechanism responsible for this angiogenesis is unknown. Vascular endothelial growth factor (VEGF) is a potent inducer of endothelial cells, which may contribute to chronic inflammation and angiogenesis. We sought to investigate the molecular mechanisms underlying increased vascularity, and we examined the mRNA expression of VEGF and its receptors (flt-1 and flk-1) within bronchial biopsy specimens from asthmatic patients and normal control subjects. Endobronchial biopsy specimens were examined immunocytochemically by staining with anti-type IV collagen mAb to evaluate vessel density by using computer-assisted image analysis. Specimens were also analyzed for the presence of the mRNAs of VEGF and its receptors with in situ hybridization. The extent of airway vascularity was increased in asthmatic subjects compared with that in control subjects (P <.01). Asthmatic subjects exhibited a greater expression of VEGF, flt-1, and flk-1 mRNA(+) cells in the airway mucosa compared with that in control subjects (P <.001 for each comparison). The degree of vascularity was associated with the number of VEGF, flt-1, and flk-1 mRNA(+) cells. Numbers of cells expressing VEGF mRNA inversely correlated with airway caliber (r = -0.83, P <.01) and airway hyperresponsiveness (r = -0.97, P <.001). Colocalization studies showed that macrophages, eosinophils, and CD34(+) cells were the major sources of VEGF; CD34(+) cells, macrophages, and T cells expressed both flt-1 and flk-1. These findings provide evidence that VEGF may play an important role in angiogenesis and subsequent airway remodeling in bronchial asthma.

Hoshino M ，Nakamura Y ，Hamid QA 《JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY》

Immunohistochemical localization of vascular endothelial growth factor (VEGF) and its two specific receptors, Flt-1 and KDR, in the porcine placenta and non-pregnant uterus.

Placental angiogenesis and growth are crucial elements in embryonic and later fetal development. Vascular endothelial growth factor (VEGF) and its specific receptors Flt-1 (VEGFR-1) and KDR (VEGFR-2) compose potent ligand receptor systems involved in angiogenesis and microvascular hyperpermeability. In the present immunohistochemical study, VEGF, Flt-1 and KDR were localized in uterus of cyclic non-pregnant pigs and in the porcine epitheliochorial placenta throughout gestation. Emphasis was placed on early gestational stages, where morphological studies have demonstrated extensive angiogenesis during initial placentation. The results revealed a high correlation in spatiotemporal distribution between the ligand and its receptors and a surprising demonstration of VEGF receptors in several non-endothelial cells. In non-pregnant pigs, VEGF, Flt-1 and KDR exhibited moderate to intense staining in uterine luminal epithelium and smooth muscle cells of the vessel walls. Endothelial cells of arteries and arterioles revealed labelling for Flt-1 and KDR, whereas the uterine glandular epithelium displayed intense KDR immunoreactivity at the late luteal phase. During gestation the uterine luminal epithelium demonstrated weak ligand and receptor immunostaining in the first half of early gestation [< or = 21 days post coitus (p.c.)], whereas later stages (> or = 21 days p.c.) displayed intense immunolabelling. Endothelial cells, smooth muscle cells of the vessel walls and uterine glandular epithelium revealed intense ligand and receptor immunoreactivity throughout gestation. In the fetal part of the placenta, VEGF, Flt-1 and KDR immunostaining displayed moderate to intense reactivity in the trophoblast throughout gestation, except during the second half of early gestation (days 21-30 p.c.). Fetal vessel walls were also immunopositive for VEGF, Flt-1 and KDR. Taken together, the results imply that the VEGF, Flt-1 and KDR ligand receptor system participate in the regulations of porcine placentation and that it in addition to its angiogenic properties also may influence the cellular differentiation and transport capabilities in uterine luminal as well as glandular epithelium and the trophoblast.

Winther H ，Ahmed A ，Dantzer V 《PLACENTA》

[Expressions of and the effect of smoking on vascular endothelial growth factor and induced nitric oxide synthase in lung tissues of chronic obstructive pulmonary disease patients].

To investigate the expressions of and the effect of smoking on vascular endothelial growth factor (VEGF) and induced nitric oxide synthase (iNOS) in lung tissues of chronic obstructive pulmonary disease (COPD) patients. The peripheral lung tissues were obtained from 46 patients with lung carcinoma. They were divided into three groups according to their habit of smoking and lung function, 19 smokers with moderate COPD, 12 smokers and 15 nonsmokers with normal lung function. The expression of VEGF and iNOS was detected by immunohistochemistry. Expressions of VEGF and iNOS were increased in lung tissues of smokers without COPD (1.50 +/- 0.39, 1.45 +/- 0.41) compared with nonsmokers without COPD (1.18 +/- 0.33, 1.09 +/- 0.41) (each P < 0.05), and were significantly increased in lung tissues of smokers with moderate COPD (2.19 +/- 0.51, 2.39 +/- 0.45) compared with nonsmokers without COPD (each P < 0.01). The expression of VEGF in lung tissues was significantly correlated with the expression of iNOS (r = 0.78, P < 0.01), but was inversely correlated with FEV(1) (r = -0.67, P < 0.01). Expressions of VEGF and iNOS were upregulated in lung tissues of smokers and patients with moderate COPD. Overexpression of iNOS and VEGF may participate in the mechanism of airway and vascular remodeling, and airflow limitation in COPD.

Huo JM ，Chen JY ，Kong YJ ，Shi YZ ... -  《-》

Budesonide/formoterol decreases expression of vascular endothelial growth factor (VEGF) and VEGF receptor 1 within airway remodelling in asthma.

Angiogenesis and microvascular remodelling may play a vital role in the chronic inflammatory process within asthma. One of the most important factors involved in angiogenesis is vascular endothelial growth factor (VEGF). In this study we hypothesised that an increased expression of VEGF may be involved in airway remodelling in asthma patients. To this end, we compared the histology and expression levels of VEGF and one of its receptors (VEGFR1) in bronchial tissues of patients with asthma compared with control patients. We also investigated the effect of treatment with budesonide/formoterol (Symbicort; AstraZeneca, Lund, Sweden) in the relationship between VEGF and airway remodelling. Bronchial tissues were obtained from patients attending the West China Hospital from April to November 2006. Thirteen patients were diagnosed with moderate asthma and 10 others were treated as control. Histological and immunohistochemical comparisons between asthmatic and control patients were made at baseline, and (for asthmatic subjects) following 6 months of treatment with budesonide/formoterol. Compared with control patients, asthmatic patients had significantly decreased respiratory parameters, including forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV(1)) (% predictive). Furthermore, patients with asthma had submucosal gland hyperplasia, increased smooth muscle mass, increased subepithelial fibrosis and neovascularisation. Asthmatic patients also exhibited increased expression of VEGF and VEGFR1 within epithelial cells. The increased expression of VEGF and its receptor correlated well with airway remodelling, airflow obstruction and airway hyper-responsiveness. After treatment with budesonide/formoterol for 6 months, the expression of VEGF and VEGFR1 was decreased, with correlatory decreased airway remodelling in patients with asthma. The increased expression of VEGF and VEGFR(1) in asthmatic patients is accompanied by an increased number and size of blood vessels in asthmatic airways, as well as airway remodelling. Budesonide/formoterol therapy for 6 months can decrease the expression of VEGF and VEGFR(1) alongside airway remodelling in asthma. The inhibition of VEGF and its receptor may be a good therapeutic strategy for asthma.

Wang K ，Liu CT ，Wu YH ，Feng YL ，Bai HL ... -  《ADVANCES IN THERAPY》