Minimally invasive colon resection is associated with a transient increase in plasma sVEGFR1 levels and a decrease in sVEGFR2 levels during the early postoperative period

Introduction  Plasma vascular endothelial growth factor (VEGF) levels are elevated for 2–4 weeks after minimally invasive colorectal resection (MICR). VEGF induces wound and tumor angiogenesis by binding to endothelial cell (EC)-bound VEGF-receptor 1 (VEGFR1) and VEGFR2. Soluble receptors (sVEGFR1, sVEGFR2) sequester VEGF in the blood and decrease VEGF’s proangiogenic effect. The importance of the MICR-related VEGF changes depends on the effect of surgical procedures on sVEGFR1 and sVEGFR2; this study assessed levels of these proteins after MICR for benign indications. Methods  Blood samples were taken (n = 39) preoperatively (preop) and on postoperative days (POD) 1 and 3; in most cases a fourth sample was drawn between POD 7 and 30. sVEGFR1 and sVEGFR2 levels were measured via enzyme-linked immunosorbent assay (ELISA), which detects free and VEGF bound soluble receptor. Late samples were bundled into POD 7–13 and POD 14–30 time points. Results are reported as mean and standard deviation. The data was assessed with paired-samples t-test. Results  Preop, mean plasma sVEGFR2 level (9,203.7 ± 1,934.3 pg/ml) was significantly higher than the sVEGFR1 value (132.5 ± 126.2 pg/ml). sVEGFR2 levels were significantly lower on POD 1 (6,957.8 ± 1,947.7 pg/ml,) and POD 3 (7,085.6 ± 2,000.2 pg/ml), whereas sVEGFR1 levels were significantly higher on POD 1 (220.0 ± 132.8 pg/ml) and POD 3 (182.7 ± 102.1 pg/ml) versus preop results. No differences were found on POD 7–13 or 14–30. Conclusions  sVEGFR2 values decreased and sVEGFR1 levels increased early after MICR; due to its much higher baseline, the sVEGFR2 changes dominate. The net result is less VEGF bound to soluble receptor and more free plasma VEGF.     

Plasma levels of angiostatin and endostatin remain unchanged for the first 3?weeks after colorectal cancer surgery

Introduction  

Angiostatin and endostatin are endogenous inhibitors of angiogenesis with anticancer effects. After minimally invasive colorectal resection (MICR), blood levels of the proangiogenic factors vascular endothelial growth factor (VEGF) and angiopoetin 2 (Ang-2) are elevated for 2–4 weeks. Also, postoperative human plasma from weeks 2 and 3 after MICR has been shown to stimulate endothelial cell proliferation and migration, which are critical to angiogenesis. This proangiogenic state may stimulate tumor growth early after MICR. Surgery’s impact on angiostatin and endostatin is unknown. This study’s purpose is to determine perioperative plasma levels of these two proteins in colorectal cancer (CRC) patients undergoing MICR.     

Minimally invasive colon resection is associated with a persistent increase in plasma PlGF levels following cancer resection

Background  

Minimally invasive colorectal resection (MICR) is associated with persistently elevated plasma VEGF levels that may stimulate angiogenesis in residual tumor foci. Placenta growth factor (PlGF) stimulates neovascularization in tumors by modulating VEGF’s effects. This study’s purpose was to determine the impact of MICR on blood PlGF levels in cancer patients (Study A) and to compare PreOp levels in patients with cancer and benign (BEN) disease (Study B).     

Minimally invasive colorectal resection for cancer is associated with a short-lived decrease in soluble Tie-2 receptor levels, which may transiently inhibit VEGF-mediated angiogenesis (via altered blood levels of free Ang-1 and Ang-2)

Background  

Angiopoetin- (Ang-) 1 inhibits and Ang-2 promotes VEGF-mediated angiogenesis via binding to endothelial cell-bound Tie-2 receptor (Tie-2). After minimally invasive colorectal resection (MICR), Ang-1 levels decrease and Ang-2 levels increase, which may stimulate angiogenesis in wounds and residual tumor foci. Soluble Tie-2 (sTie-2) modulates the effects of free Ang-1 and Ang-2 by binding to them. This study assessed perioperative MICR plasma sTie-2 levels.     

Minimally invasive colorectal resection is associated with a rapid and sustained decrease in plasma levels of epidermal growth factor (EGF) in the colon cancer setting

Background  

Epidermal growth factor (EGF) stimulates tumor growth directly via tumor cell EGF receptors or indirectly via its proangiogenic effects. This study’s purpose was to determine the impact of minimally invasive colorectal resection (MICR) on postoperative (postop) plasma EGF levels in the colorectal cancer (CRC) and benign disease settings and to see if preoperative (PreOp) EGF levels are altered in cancer patients.     

Plasma from the second and third weeks after open colorectal resection for cancer stimulates in vitro endothelial cell growth,migration, and invasion

Introduction  

Angiogenesis is central to wound healing and tumor growth. Postoperative (postop) plasma from weeks 2 and 3 after minimally invasive colorectal resection (MICR) stimulates endothelial cell (EC) migration (MIG), invasion (INV), and proliferation (all vital to angiogenesis) compared with preoperative (preop) plasma results and may promote postop tumor growth. The purpose of this study was to determine whether plasma from open colorectal resection (OCR) patients has similar proangiogenic EC effects in vitro.     

Plasma soluble vascular adhesion molecule-1 levels are persistently elevated during the first month after colorectal cancer resection

Introduction

Plasma from the second and third weeks after minimally invasive colorectal resection (MICR) has high levels of the proangiogenic proteins VEGF and angiopoietin 2 and also stimulates, in vitro, endothelial cell (EC) proliferation and migration, which are critical to wound and tumor angiogenesis. Soluble vascular cell adhesion molecule-1 (sVCAM-1) stimulates EC chemotaxis and angiogenesis. The impact of MICR on blood levels of sVCAM-1 is unknown. This study’s purpose was to determine plasma sVCAM-1 levels after MICR in colorectal cancer (CRC) patients.

Methods

Blood samples from 90 patients (26% rectal, 74% colon) were obtained preoperatively, on postoperative days (POD) 1 and 3, and at other points during the next 2?months. The late samples were bundled into 7-day time blocks. sVCAM-1 levels were determined in duplicate via ELISA and reported as ng/ml. Student’s t test was used for data analysis (significance, P?Results The mean incision length was 7.3?±?3.1?cm, and the conversion rate was 3%. Compared with preoperative (PreOp) levels (811.3?±?233.2), the mean plasma sVCAM-1 level was significantly higher on POD 1 (905.7?±?292.4, P?P?Conclusions MICR for CRC is associated with a persistent increase in plasma sVCAM-1 levels during the first month. This sustained increase may promote angiogenesis and stimulate the growth of residual tumor cells early after surgery.     

Glucose-regulated protein 78 silencing down-regulates vascular endothelial growth factor/vascular endothelial growth factor receptor 2 pathway to suppress human colon cancer tumor growth

Background

Up to 20% of colorectal cancer (CRC) is diagnosed with distant metastasis. The combination of chemotherapy with anti-vascular endothelial growth factor (VEGF) antibody can improve patient survival. Glucose-regulated protein 78 (GRP78) has an important role in cancer progression, but little is known about its role in VEGF production in CRC. The aim of this study was to explore the mechanism of GRP78 in two human colon cancer cell lines.

Methods

We first checked the expression of GRP78 in human normal and colon cancer tissues and two colon cancer cell lines. Glucose-regulated protein 78 was knocked down using GRP78 small interfering RNA (siRNA) in HT29 and DLD-1 cells. We examined knockdown cells by the cell growth kinetics in vitro and tumor growth rate in vivo, respectively. We also investigated the effect of GRP78 siRNA on the expression of hypoxia inducible factor (HIF-1α), VEGF, and VEGF receptor 2 (VEGFR2).

Results

Compared with their adjacent normal tissue, we detected high expression levels of GRP78 of surgically removed colon cancer tissues. Using GRP78 siRNA, we reduced the expression of GRP78 in HT29 and DLD-1 cells. The GRP78 knockdown cells had a lower proliferation rate with fewer colony-forming units in vitro and produced smaller tumors in vivo. In dissecting the mechanism underlying the reduced cell growth, we found that the down-regulation of GRP78 decreased the production of HIF-1α, VEGF, and VEGFR2 and suppressed angiogenesis.

Conclusions

Silencing GRP78 not only inhibits tumor, but also decreases the expression of VEGF and VEGFR2. Collectively, therapy targeting for GRP78 may inhibit the formation of colon cancer tumors via the HIF-1α/VEGF/VEGFR2 pathway.     

Expression of vascular endothelial growth factor and angiopoietins in human corpus cavernosum

OBJECTIVE

To evaluate the expression of the angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietins (Ang) 1 and 2, in normal human penile erectile tissue.

MATERIALS AND METHODS

Penile fragments were removed from four young healthy organ donors (aged 17–28 years), and processed for immunohistochemical studies for VEGF, Ang1 and Ang2, and their specific receptors (VEGFR1 and 2, and Tie2, respectively). Molecular analysis was used to confirm the expression of VEGF and Angs in erectile tissue.

RESULTS

VEGF and VEGFR1 expression was restricted to smooth muscle cells (SMCs). VEGFR2 was detected mainly in the endothelium lining and to a lesser extent in the SMC. Ang1 had a scattered distribution mostly in the perivascular SM layer, showing co‐localization with VEGF. Tie2 was faintly detected in the endothelial cells. Ang2 was not detected by immunohistochemical studies, but the use of the same antibody in molecular analysis confirmed Ang2 expression in human corpus cavernosum.

CONCLUSIONS

We show for the first time the co‐localization of VEGF and Ang1 in the SMC, suggesting an interaction for vessel stabilization. Ang2 seems to be available for neoangiogenesis, if challenged. Studies of endothelial markers, growth factors and specific receptors are useful for understanding vascular organization and angiogenesis in normal human erectile tissue. This knowledge will be fundamental for developing newer therapeutic approaches to prevent or even cure erectile dysfunction.     

Effect of mitomycin C on concentrations of vascular endothelial growth factor and its receptors in bladder cancer cells and in bladders of rats intravesically instilled with mitomycin C

What’s known on the subject? and What does the study add? Mitomycin C is widely used for treatment of bladder cancer, however disease progression after mitomycin C treatment is common. We found that intravesical mitomycin C treatment increases urinary vascular endothelial growth factor (VEGF) and bladder VEGF receptor‐2 protein and mRNA in rats. Mitomycin C also increases VEGF mRNA and VEGF receptor‐2 protein and mRNA levels in bladder cancer cells. Therefore, we speculate that mitomycin C may increase the angiogenic potential of both cancer and normal cells.

OBJECTIVES

• ? To examine, using in vitro and in vivo models, the largely unexamined effect of mitomycin C (MMC), an effective intravesical treatment for superficial bladder cancer and carcinoma in situ, on expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor‐2 (VEGFR‐2), which mediates many of the angiogenic properties of VEGF.
• ? To measure, as a positive control, concentrations of the inhibitor of apoptosis, survivin, as an assessment of MMC effectiveness.
• ? To measure MMC‐induced changes in proliferation in the presence and absence of VEGF‐A small interfering RNA (siRNA).

MATERIALS AND METHODS

• ? After treatment with increasing MMC concentrations (5–200 µg/mL), we measured proliferation, as well as VEGF, survivin, VEGF receptor‐1 (VEGFR‐1) and VEGFR‐2 concentrations in RT‐4 and T‐24 bladder cancer cells.
• ? The effect of pre‐treatment of VEGF siRNA and survivin siRNA on MMC‐induced decreases in proliferation was measured.
• ? Urinary VEGF concentrations and bladder and kidney concentrations of VEGF‐A, VEGFR‐1, VEGFR‐2 and interleukin‐6 (IL‐6) mRNA were measured in rats intravesically instilled with saline or MMC (200 µg/mL).

RESULTS

• ? Although MMC treatment inhibited cell proliferation and decreased survivin mRNA expression in T‐24 and RT4 cells, MMC (12–50 µg/mL) increased VEGF‐A mRNA and VEGFR‐2 mRNA and protein expression.
• ? Pre‐treatment with VEGF‐A siRNA or survivin siRNA before MMC treatment reduced proliferation more than MMC alone.
• ? MMC‐induced reductions in proliferation were reduced additively by pre‐treatment with survivin siRNA, but were potentiated by pre‐treatment with VEGF‐A siRNA.
• ? VEGFR‐2 mRNA and protein concentrations and urinary VEGF concentrations were increased in bladders of rats instilled with MMC.

CONCLUSIONS

• ? Intravesically instilled MMC increases urinary VEGF and bladder VEGFR‐2 protein and mRNA in rats.
• ? MMC increases VEGF mRNA and VEGFR‐2 protein and mRNA concentrations in bladder cancer cells. Therefore, we speculate that MMC could increase the angiogenic potential of both cancer and normal cells.
• ? In cancer cells this effect is largest at lower MMC concentrations.
• ? Combining MMC with agents that reduce EGF concentrations could be of value in treatment of transitional cell carcinoma of the bladder (TCC).

     

Prognostic Significance of c-erbB-2 and Vascular Endothelial Growth Factor in Colorectal Liver Metastases

Background  

The prognostic value of c-erbB-2 and vascular endothelial growth factor (VEGF) expression in colorectal liver metastases (CLM) is unclear. The purpose of this study was to clarify the relationship of c-erbB-2 and VEGF with the clinicopathological parameters and the survival results in CLM.     

Soluble VEGFR1 reverses BMP2 inhibition of intramembranous ossification during healing of cortical bone defects

BMP2 is widely used for promotion of bone repair and regeneration. However, bone formation induced by BMP2 is quite variable. Bone forming progenitor cells in different locations appear to respond to BMP2 in different ways, and repair outcomes can vary as a consequence of modulating effects by other factors. In this study, we have examined the effects of VEGF on BMP2‐induced repair of a cortical bone defect, a 1 mm diameter drill hole, in the proximal tibia of mice. Treatment of the defect with either a bolus of PBS or soluble VEGFR1 (sVEGFR1), a decoy receptor for VEGF, had the same effects on bone formation via intramembranous ossification in the defect and cartilage formation and injured periosteum, during the healing process. In contrast, treatment with BMP2 inhibited intramembranous bone formation in the defect while it promoted cartilage and endochondral bone formation in the injured periosteum compared with mice treated with PBS or sVEGFR1. The inhibitory effect of BMP2 on bone formation was unlikely due to increased osteoclast activity and decreased invasion of blood vessels in the defect. Most importantly, co‐delivery of BMP2 and sVEGFR1 reversed the inhibition of intramembranous bone formation by BMP2. Furthermore, the decreased accumulation of collagen and production of bone matrix proteins in the defect of groups with BMP2 treatment could also be prevented by co‐delivery of BMP2 and sVEGFR1. Our data indicate that introducing a VEGF‐binding protein, such as sVEGFR1, to reduce levels of extracellular VEGF, may enhance the effects of BMP2 on intramembranous bone formation. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1461–1469, 2017.

     

Effects of adrenomedullin and vascular endothelial growth factor on ischemia/reperfusion injury in skeletal muscle in rats

Background

In this study we investigated the effects of adrenomedullin (AM) and vascular endothelial growth factor (VEGF) on skeletal muscle ischemia/reperfusion (I/R) injury in a rat model.

Materials and methods

Thirty-six Wistar rats were randomized into six groups (n = 6). Laparotomy was performed in all groups under general anesthesia. Nothing else was done in Group S (Sham). The Group I/R underwent I/R performed by clamping and declamping of the infrarenal abdominal aorta for 120 min, respectively. Group VEGF and Group AM received intravenous infusion of VEGF (0.8 μg/kg) or AM (12 μg/kg) respectively, without I/R. Group I/R + VEGF and Group I/R + AM received intravenous infusion of VEGF (0.8 μg/kg) or AM (12 μg/kg) immediately after 2 h period of ischemia, respectively. At the end of reperfusion period, skeletal muscle samples of lower extremity were taken from all groups for biochemical and histopathologic examinations.

Results

Tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO), and hypoxia inducible factor 1 alpha (HIF 1α) were found to be significantly higher in Group I/R than the levels in Group S (P < 0.05). Tissue levels of MDA, SOD, NO, and HIF 1α were significantly lower in Group I/R + AM compared with the levels in Group I/R (P < 0.05). In Group I/R + VEGF, tissue levels of MDA and NO were significantly lower than the levels in Group I/R (P < 0.05). No statistically significant difference was found in the tissue levels of catalase among the groups. Histologic examination revealed a larger central muscular necrosis than the peripheral necrosis, red blood cells in the lumens of capillary vessels, and a stronger atrophy and elliptical or round shape in muscle fibers in Group I/R. Terminal deoxynucleotidyl transferase mediated dUPT nick end labeling (TUNEL)-positive cell count was significantly lower in groups I/R + AM and I/R + VEGF than Group I/R (P < 0.0001, P < 0.0001, respectively).

Conclusions

These results indicate that AM and VEGF have protective effects on I/R injury in skeletal muscle in a rat model.     

Alterations in plasma soluble vascular endothelial growth factor receptor-1 (sFlt-1) concentrations during coronary artery bypass graft surgery: relationships with post-operative complications

Background  

Plasma concentrations of sFlt-1, the soluble form of the vascular endothelial growth factor receptor (VEGF), markedly increase during coronary artery bypass graft (CABG) surgery with extracorporeal circulation (ECC). We investigated if plasma sFlt-1 values might be related to the occurrence of surgical complications after CABG.     

Vascular endothelial growth factor receptor-2 inhibition in experimental murine colitis

Background

In the setting of inflammatory bowel disease, inflammation is associated with a simultaneous increase in angiogenesis; moreover, elevated vascular endothelial growth factor (VEGF) levels implicate angiogenesis as a pathologic contributor to disease severity. We hypothesize that selectively inhibiting vascular endothelial growth factor receptor-2 (VEGFR2) in a model of murine colitis will reduce angiogenesis, resulting in decreased inflammation and disease severity, providing mechanistic insight into the role of pathologic angiogenesis in IBD.

Materials and methods

In a dextran sodium sulfate model of murine colitis, anti-VEGFR2 monoclonal antibody (DC101) or placebo was administered. Clinical assessments followed by histologic and molecular tissue analysis were performed to quantify inflammation, microvessel density (MVD), VEGF and VEGFR2 gene expression, and phosphorylated mitogen-activated protein kinase protein expression.

Results

Weight loss began after d 6 with the treatment group demonstrating a more favorable percent weight change. Inflammation and MVD were similar between cohorts, both increasing in parallel toward a plateau. VEGF and VEGFR2 messenger RNA expression were not significantly different, but phosphorylated mitogen-activated protein kinase was elevated in the DC101 cohort (P = 0.03).

Conclusions

Despite a more favorable weight change profile in the treated group, no difference was observed between cohorts regarding clinical disease severity. However, a parallel rise in inflammation and MVD was observed coinciding with weight loss, suggesting their relationship in IBD. VEGFR2 downstream signaling was significantly elevated in the treated cohort, possibly by VEGF-independent signal transduction. Early and effective inhibition of angiogenesis by limiting downstream VEGF signaling or targeting multiple angiogenic pathways may block angiogenesis, thereby reducing disease severity and provide evidence toward the mechanism and clinical benefit of antiangiogenics in the setting of IBD.     

A role of cytokines in OK-432 injection therapy for cystic lymphangioma: an approach to the mechanism

Purpose: This study examines cytokine levels of aspirates from cystic lymphangiomas after injection of OK-432 and over the course of several weeks to better understand the process of tumor regression.Methods: Fluids aspirated from lymphangioma cysts of 3 patients were collected sequentially before and after OK-432 injection. Mononuclear cells (MNCs) were separated and cultured with or without OK-432. Vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGFR1), sVEGFR2, transforming growth factor beta-1 (TGF-β1), interleukin (IL)-6, IL-8, IL-12+p40, tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels in the supernatants of the aspirates and the culture supernatants of MNCs were then measured by ELISA.Results: The aspirates exhibited a marked elevation in IL-6, IL-8, VEGF, and TGF-β1 levels for a few weeks after the OK-432 injection. IL-6, IL-8, IL-12+p40, TNF-α, and IFN-γ levels were elevated in the culture supernatants of the MNC cultured with OK-432 for up to 9 days. All the tumors regressed significantly, with sclerotic change, within 3 months after OK-432 injection.Conclusions: Cytokine production is maintained for a few weeks after OK-432 injection. Fibrotic changes may be another main mechanism in tumor regression in addition to cytotoxic effects on lymphangioma cells. A close relationship between cytokines from intracystic cells and lymphangioma cells is suggested.     

Minimally invasive colorectal resection is associated with significantly elevated levels of plasma matrix metalloproteinase 3 (MMP-3) during the first month after surgery which may promote the growth of residual metastases

Introduction

MMP-3, a member of the matrix metalloproteinase (MMP) family, is involved in the breakdown of the extracellular matrix in tissue remodeling and may also play a role in cancer progression and metastasis. Minimally invasive colorectal resection (MICR) may increase plasma MMP-3 levels directly via surgical trauma or indirectly due to surgery-associated elevations in TNF-α and IL1 which are regulators of MMP-3. This study’s purpose was to evaluate plasma MMP-3 levels during the first month after MICR for colorectal cancer.

Methods

Patients enrolled in an IRB approved data/plasma bank who underwent elective MICR for CRC. Blood plasma samples had been collected preoperatively, on postoperative day (POD) 1, 3 and at varying postoperative time points and were stored at ?80 °C. The late samples (POD 7–41) were bundled into 7 day time blocks and considered as single time points. MMP-3 levels were analyzed in duplicate via ELISA and the results reported as mean ± SD. The paired t test was used for analysis (significance, p < 0.008 after Bonferroni’s correction).

Results

A total of 73 CRC patients who underwent MICR met the inclusion criteria. The mean PreOp MMP-3 level was 14.9 ± 7.8 ng/ml (n = 73). Significantly elevated mean plasma levels were noted on POD 1 (21.4 ± 14.7 ng/ml, n = 73, p < 0.0001), POD 3 (37.9 ± 21.5 ng/ml, n = 72, p < 0.0001), POD 7–13 (22.0 ± 13.0 ng/ml, n = 56, p < 0.0001), POD 14–20 (21.9 ± 10.3 ng/ml, n = 20, p = 0.003), and on POD 21–27 (21.9 ± 11.43 ng/ml, n = 20, p = 0.002) when compared to PreOp levels. Plasma levels returned to the PreOp baseline at the POD 28–41 time point (n = 16, p = 0.07).

Conclusion

Plasma MMP-3 levels remained significantly elevated from baseline for 4 weeks after MICR for CRC. The early postoperative increase in MMP-3 levels may be due to the surgery-related acute inflammatory response; the elevation noted during weeks 2–3 may be related to wound healing. Increased MMP-3 levels may promote metastases or the growth of residual cancer.     

Roles of VEGF-C and Smad4 in the Lymphangiogenesis,Lymphatic Metastasis,and Prognosis in Colon Cancer

Background/Aims  

We combined two different signal pathways on transforming growth factor β1 (TGF-β1)-Smad and vascular endothelial growth factor C (VEGF-C)/VEGF receptors for exploring changes in pathway members and their influence on lymphangiogenesis and clinicopathological features.     

Effects of inhaled fluticasone on angiogenesis and vascular endothelial growth factor in asthma

BACKGROUND: Subepithelial hypervascularity and angiogenesis in the airways are part of structural remodelling of the airway wall in asthma, but the effects of inhaled corticosteroids (ICS) on these have not been explored. Increased vascularity in asthma may contribute to a number of functional abnormalities. A study was undertaken to explore angiogenic modulation by ICS and its likely regulation via vascular endothelial growth factor (VEGF), its receptors and the angiopoietins. METHODS: A placebo-controlled intervention study with ICS in asthma was performed, examining vascularity, VEGF, its receptors (VEGFR1 and VEGFR2), and angiopoietin-1 (Ang1) to assess which of these factors were changed in the asthmatic airways after ICS treatment. Airway wall biopsy specimens, lavage fluid and cells were obtained from 35 patients with mild asthma randomised to receive ICS or placebo for 3 months, after which bronchoscopic examination and sample collection were repeated. Immunohistochemistry and image analysis were used to obtain quantitative measures of vessels, angiogenic sprouts, VEGF, VEGFR1, VEGFR2 and Ang1 staining in airway biopsy specimens. ELISA was used to assess VEGF concentrations in the lavage fluid. RESULTS: Vessel, VEGF and sprout staining were decreased after 3 months of ICS treatment. VEGF levels remained unchanged. VEGF receptors and Ang1 staining were not reduced after treatment. CONCLUSIONS: The findings of this study support an effect of ICS in downregulating angiogenic remodelling in the airways in asthma, associated with decreasing VEGF activity within the airway wall. The environment of the airways after treatment with ICS, with changes in the balance between VEGF, its receptors, Ang1 and sprouts, appears to be less angiogenic than in untreated asthma.     

Colorectal resection,both open and laparoscopic-assisted,in patients with benign indications is associated with proangiogenic changes in plasma angiopoietin 1 and 2 levels

Introduction  Plasma vascular endothelial growth factor (VEGF) levels are increased after surgery and may stimulate tumor growth after cancer resection. Angiopoietin 1 (Ang 1) and Ang 2 are proteins that impact VEGF-related angiogenesis (VRA). Ang 1 stabilizes mature vessels and inhibits VRA, whereas Ang 2 destabilizes vessels and promotes VRA. The ratio of Ang 1 to Ang 2 reflects the net effect; a low ratio promotes VRA. This study’s purpose was to determine the impact of open and minimally invasive (MIS) colorectal resection (CR) for benign indications on plasma Ang 1 and 2 levels. Methods  A total of 30 patients operated by MIS and 26 operated by open procedure were studied. Plasma was obtained preoperatively (PO) and on postoperative days (POD) 1 and 3. Plasma Ang 1 and Ang 2 levels were assessed via enzyme-linked immunosorbent assay (ELISA) in duplicate. Data were compared using Wilcoxon’s matched-pair test and the Mann–Whitney U-test (significance p < 0.05). Results  Indications, types of resection, and morbidity for the groups were similar. The mean MIS incision length was 4.7 ± 1.6 cm while it was 16.8 ± 7.1 cm for the open group (p = 0.0001). For both groups Ang 2 levels were significantly higher and the Ang 1 to Ang 2 ratio was significantly lower on POD 1 and 3 compared with preoperative results. Ang 1 levels were significantly decreased on POD 1 and 3 in the MIS group but only on POD 1 in the open group. For unclear reasons, preoperative Ang 1 levels and Ang 1 to Ang 2 ratios were significantly different between the groups, which precludes comparison of the postoperative results between groups. Conclusion  CR for benign pathology results in higher Ang 2 levels, lower Ang 1 levels, and lower Ang 1 to Ang 2 ratios early after surgery. These alterations are proangiogenic. These results, plus the already noted VEGF increases, suggest that surgery results in proangiogenic plasma protein changes that may stimulate tumor growth early after surgery. The duration of the Ang 1 and 2 changes needs to be determined. An erratum to this article can be found at