Vasohibin-1 Level Research Articles

Elevated serum vasohibin-1 levels in atopic dermatitis: Implications for disease chronicity.

Atopic dermatitis (AD) is often characterized by chronic skin changes of dermal fibrosis, typically regulated by inflammatory and angiogenic factors. However, the significance of angiogenesis inhibitory factors in the development of AD is poorly understood. The present study investigated the potential role of an angiogenesis inhibitory factor, vasohibin-1 (VASH1), in AD by evaluating serum and skin VASH1 levels and their correlation with clinical features. The results showed that VASH1 expression levels in both the serum and skin of patients with AD were significantly elevated compared to healthy controls. Immunohistochemical staining of AD skin showed increased VASH1 expression in dermal vascular endothelial cells. Notably, there was a significant correlation between serum VASH1 levels and disease duration as well as VASH1 and vascular endothelial growth factor A expression levels in the skin tissue of patients with AD. These results may suggest a pathogenesis of increased angiogenesis and associated elevated inhibitory processes accompanying inflammation in the chronic phase of AD.

Is Serum Vasohibin-1 Level Associated with the Development of Kidney Disease in Diabetic Patients?

Is Serum Vasohibin-1 Level Associated with the Development of Kidney Disease in Diabetic Patients?

Differences and Clinical Significance of Serum 25-Hydroxyvitamin D3 and Vasohibin-1 (VASH-1) Levels in Patients with Diabetic Nephropathy and Different Renal Injuries.

We investigate the relationship between the changes of serum 25-hydroxyvitamin D3 (25(OH)D3) and vasohibin-1 (VASH-1) and renal function injury in patients with type 2 diabetic nephropathy. In this study, 143 patients with diabetic nephropathy (DN) were selected as DN group, and 80 patients with type 2 diabetes mellitus were selected as T2DM group. The serum 25 (OH) D3, VASH-1, blood glucose index, inflammation index and renal function index were compared between the two groups. According to the urinary microalbumin/creatinine ratio (UACR), the DN group was divided into microalbuminuria group (UACR range≥30.0mg/g and <300.0mg/g) and macroalbuminuria group (UACR≥300.0mg/g) for stratified comparison. The correlation between 25-hydroxyvitamin D3, VASH-1 and inflammation index and renal function index was analyzed by simple linear correlation analysis. The level of 25 (OH) D3 in DN group was significantly lower than that in T2DM group (P<0.05). The levels of VASH-1, CysC, BUN, Scr, 24h urine protein, serum CRP, TGF-β1, TNF-α and IL-6 in DN group were higher than those in T2DM group (P<0.05). The level of 25 (OH) D3 in DN patients with massive proteinuria was significantly lower than that in DN patients with microalbuminuria. The level of VASH-1 in DN patients with massive proteinuria was higher than that in DN patients with microalbuminuria (P<0.05). There was a negative correlation between 25 (OH) D3 and CysC, BUN, Scr, 24h urine protein, CRP, TGF-β1, TNF-α, IL-6 in patients with DN (P<0.05). VASH-1 was positively correlated with Scr, 24h urinary protein, CRP, TGF-β1, TNF-α and IL-6 in patients with DN (P<0.05). The level of serum 25 (OH) D3 in DN patients was considerably decreased, and the level of VASH-1 was increased, which was related to the degree of renal function injury and inflammatory response.

Akciğer Kanserli Hastalarda Serum ve Bronkoalveolar Lavaj Sıvısında Vasohibin-1 Düzeylerinin Belirlenmesi

Objective: Lung cancer constitutes 17% of all cancer cases and accounts for 23% of the deaths caused by cancer all over the world. Vasohibin-1 (VASH-1) is an angiogenesis-inhibiting factor synthesized by endothelial cells (ECs). This study aimed to examine the VASH-1 levels of the bronchoalveolar lavage (BAL) and serum in the patients with lung cancer.&#x0D; Material and Method: A total of 82 patients participated in this study. 39 and 43 of them had a benign lung disease and lung cancer, respectively. The VASH-1 levels of serum and BAL were measured using the Enzyme-Linked Immunosorbent Assay (ELISA).&#x0D; Results: The BAL VASH-1 levels of the patients in the lung cancer group were found to be statistically significantly lower than those of the patients in the benign lung disease group (p=0.032). No statistically significant difference was found between the individuals with lung cancer and benign lung disease in terms of the serum VASH-1 concentration (p=0.206). A statistically significantly moderate positive correlation was found between the serum and BAL VASH-1 levels in the benign and malignant cases (benign r=0.442, p=0.005; malignant r=0.364, p=0.016). When the lung cancer patients were categorized into pathological stages and histological types, no significant difference was found between the stages and histological types in terms of the serum and BAL fluid VASH-1 concentrations.&#x0D; Conclusions: BAL VASH-1 concentrations decreased in the lung cancer patients compared to the individuals having a benign lung disease. Considering the results reached in this study, it was thought that the BAL VASH-1 concentrations might be beneficial in distinguishing between the benign and malignant lung diseases.

Serum levels of vasohibin-1 in type 2 diabetes mellitus patients with diabetic retinopathy.

To determine whether Vasohibin-1 which is a potential clinical biomarker is an independent risk factor in patients with diabetic retinopathy. Diabetic retinopathy (DR) is a common chronic microangiopathy in type 2 diabetes mellitus (T2DM). Vasohibin-1 (VASH-1) is an angiogenesis regulator that is closely related to pathological vascularization in DM. This study aimed to determine whether the serum levels of VASH-1 were related to the occurrence of DR in T2DM patients. T2DM patients were divided into three groups: the nondiabetic retinopathy (NDR) group (n = 41), the nonproliferative diabetic retinopathy (NPRD) group (n = 40), and the proliferative diabetic retinopathy (PDR) group (n = 41). A control (CON) group consisting of 40 healthy subjects was also recruited. The serum levels of VASH-1 were measured by enzyme-linked immunosorbent assay kits. The concentration of VASH-1 in the CON groups was less significantly than that of the NDR, NPDR and PDR groups. (P < 0.05). Body mass index, fasting plasma glucose (FPG), hemoglobina1c (HbA1C), blood urea nitrogen (BUN) and diabetic durations were positively correlated with the serum concentration of VASH-1 (all P < 0.05). In univariate logistic regression analyses, the HbA1C, diabetic durations, HDL-c, eGFR and VASH1 were associated with the presence of diabetic retinopathy. Multivariate logistic regression analysis showed that duration of diabetes were significantly associated with diabetic retinopathy. We have shown that VASH-1 is associated with an increased risk of developing diabetic retinopathy. But the serum levels of VASH-1 are not independent risk factors for DR in T2DM.

Serum vasohibin-1 levels: A potential marker of dermal and pulmonary fibrosis in systemic sclerosis.

Vasohibin-1 (VASH-1) is a potent anti-angiogenic factor mainly produced by endothelial cells. In addition, VASH-1 prevents TGF-β-dependent activation of renal fibroblasts. Since systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis of multiple organs, VASH-1 may be involved in the development of this disease. In this study, we investigated the potential role of VASH-1 in SSc by evaluating the clinical correlation between serum VASH-1 levels and the expression of VASH-1 in SSc-involved skin. Serum VASH-1 levels were higher in SSc patients, especially those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, SSc patients with interstitial lung disease had significantly elevated levels of serum VASH-1 as compared to those without. Importantly, serum VASH-1 levels correlated inversely with both the percentage of predicted vital capacity and the percentage of predicted diffusion lung capacity for carbon monoxide and positively with serum KL-6 levels, but not serum surfactant protein D levels. In SSc-involved skin, VASH1 mRNA was remarkably upregulated compared with healthy control skin, but the major source of VASH-1 was not clear. Fli1 deficiency, a predisposing factor inducing SSc-like endothelial properties, did not affect VASH-1 expression in human dermal microvascular endothelial cells. Collectively, these results suggest that VASH-1 upregulation in the skin and sera is linked to dermal and pulmonary fibrotic changes in SSc, while the contribution of VASH-1 to SSc vasculopathy seems to be limited.

Vasohibin 1, a clinically relevant biomarker, contributes to pre-eclampsia.

Pre-eclampsia is a leading health threat for pregnant women which is characterised by hypertension and proteinuria. The detailed mechanism is elusive and no effective therapy is available. Predictive biomarkers are needed for accurate diagnosis. Vasohibin-1 (VASH1) is an intrinsic inhibitor of angiogenesis induced by angiogenic factors in endothelial cells. This study aimed to evaluate the role of VASH1 as a useful biomarker for pre-eclampsia. VASH1 level was examined by ELISA and immunoblotting assay in the serum and placental samples from healthy pregnant women and pre-eclampsia patients. Cellular assay was performed to assess cell migration and invasion with different levels of VASH1. The level of VASH1 was measured under different oxygen conditions by qPCR. VASH1 was highly expressed in the serum and placenta of pre-eclampsia patients. Overexpression of VASH1 led to attenuated cell migration and invasion ability and reduced levels of matrix metallopeptidase 2 and 9. VASH1 was significantly induced in primary human trophoblast cells and placental explants under hypoxic condition in hypoxia-inducible factor 1 alpha-dependent manner. Our study suggested that VASH1 could be used as a potentially novel biomarker for pre-eclampsia and its level may positively correlate with the disease status.

Can vasohibin-1, an endothelium-derived angiogenesis inhibitor, be a marker of endothelial dysfunction in hemodialysis patients?

Endothelial dysfunction (ED) is associated with high cardiovascular disease burden in hemodialysis (HD) patients. Vasohibin-1, an endothelium-derived angiogenesis inhibitor, is essential for endothelial cell survival, therefore it may be a promising marker of ED. We aimed to investigate whether vasohibin-1 levels are associated with ED markers in HD patients. Fifty HD patients and 30 healthy controls were included in the study. As markers of ED, endothelium-dependent flow-mediated dilatation (FMD), carotid intima-media thickness (CIMT), and pulse wave velocity (PWV) were examined. Serum vasohibin-1 levels were measured with ELISA. Serum vasohibin-1 levels were low (387.7±115.7 vs 450.1±140.1 P=.02), FMDs' were impaired (6.65±2.50 vs 10.95±2.86 P<.001), PWV (7.92±1.964 vs 6.79±0.96 P=.01) and CIMT (0.95±0.20 vs 0.60±0.11 P<.001) were increased in HD patients compared to healthy controls. In regression analysis, vasohibin-1 levels were not related with FMD, PWV, or CIMT. Hemodialysis patients have low serum vasohibin-1 levels but serum levels of vasohibin-1 did not show any significant relationship with FMD, PWV, and CIMT in HD patients. Since vasohibin-1 acts via paracrine pathways, serum levels may be insufficient to explain the relationship between vasohibin and ED. Local vasohibin-1 activity on tissue level may be more important instead of circulating levels.

Plasma vasohibin-1 and vasohibin-2 are useful biomarkers in patients with esophageal squamous cell carcinoma

Vasohibins (VASH), which are angiogenesis regulators, consist of Vasohibin-1 (VASH1) and Vasohibin-2 (VASH2). VASH1 is an angiogenesis inhibitor, while VASH2 is a proangiogenic factor. Patients with esophageal squamous cell carcinoma (ESCC) with high tumor expression levels of VASH1 and VASH2 have been reported to show a poor prognosis. The clinical significance of VASH concentrations in the blood of patients with ESCC has not yet been investigated. Plasma samples from 89 patients with ESCC were analyzed, and the relationships between the plasma VASH concentrations and the clinicopathological factors of the patients were evaluated. Immunohistochemical examination (IHC) of the resected tumor specimens for VASH was performed in 56 patients, and the correlation between the plasma VASH concentrations and tumor expression levels of VASH was analyzed. The patient group with high plasma concentrations of VASH1 showed a higher frequency of lymph node metastasis (P = 0.01) and an invasive growth pattern (P = 0.05). Furthermore, poorly differentiated cancer occurred at a higher frequency in the patient group with high plasma concentrations of VASH2 (P < 0.01). High tumor expression levels of VASH1 were encountered more frequently in the patient group with high plasma concentrations of VASH1 (P = 0.03), and high tumor expression levels of VASH2 were encountered more frequently in the patient group with high plasma concentrations of VASH2 (P = 0.04). In patients with ESCC, high plasma concentrations were associated with poor clinical outcomes for both VASH1 and VASH2. We propose that results indicate that plasma VASH1 and VASH2 are useful biomarkers in patients with ESCC.

Expression of vasohibin-1, MACC1 and KA11 proteins in serous ovarian cancer and their clinical significance

To examine the expression of vasohibin-1, metastasis-associated in colon cancer-1 (MACC1) and KAI1 proteins in serous ovarian cancer and their clinical significance. Methods: In 124 specimens of serous ovarian cancer (serous ovarian cancer group) and 30 specimens of ovarian serous cystadenoma (ovarian serous cystadenoma group), the expression of vasohibin-1, MACC1 and KAI1 protiens were detected by immunohistochemistry ElivisionTM method. Results: In the serous ovarian cancer group, the positive rates of vasohibin-1 and MACC1 proteins were 48.4% and 58.1%, respectively, which were both higher than those in the ovarian serous cystadenoma group (10.0% and 13.3%, respectively); while the positive rate of KAI1 protein in the serous ovarian cancer group was 33.9%, which was lower than that in the ovarian serous cystadenoma group (86.7%), there were significant differences between the 2 groups (all P<0.05). In the serous ovarian cancer group, the expression of the 3 proteins were closely related to the pathological grade, Federation International of Gynecology and Obstetrics (FIGO) stage and pelvic lymph node metastasis (all P<0.05). The KAI1 protein was negatively correlated with the levels of vasohibin-1 and MACC1 (r=-0.500, -0.600, respectively, both P<0.01); while there was a positive correlation between the vasohibin-1 and the MACC1 (r=0.518, P<0.01). Kaplan-Meier survival analysis showed that the over-expression of vasohibin-1, MACC1 and the low-expression of KAI1 protein were related to the survival rates (all P<0.05). Multi-factor analysis showed that the expression of vasohibin-1, KAI1 protein and the FIGO stage were independent prognosis factors for radical operation of serous ovarian cancer (RR=2.185, 3.893, 0.413; 95% CI=1.263-3.779, 2.190-6.921, 0.251-0.681; all P<0.05). Conclusion: The up-regulation of vasohibin-1, MACC1 and down-regulation of KAI1 in serous ovarian cancer are related to the tumor differentiation, clinical stage, metastasis and prognosis. Combined detection of these indexes is useful in predicting the progression and prognosis of serous ovarian cancer.

Expression and clinical significance of serum vasohibin-1 in type 2 diabetes mellitus patients

Objective To investigate the expression and clinical significance of vasohibin-1 (VASH-1) in patients with type 2 diabetes mellitus. Methods From November 2015 to December 2017, four hundred and twenty-two patients with T2DM in Chaoyang Central Hospital were selected and divided into three groups according to the urinary albumin excretion rate (UACR): normal albuminuria group ( UACR 300 mg / g, 130 cases). Three hundred healthy subjects in Chaoyang Central Hospital during the same period were selected as control group.The levels of serum VASH-1 and transforming growth factor -β1(TGF-β1) in each group were determined by enzyme linked immunosorbent assay. Results VASH-1 and TGF-β1 in diabetic group and control group were (579±236) ng/L, (350±141) ng/L and (18.92±2.21) μg/L, (5.69±0.70) μg/L, respectively.There were significant differences between the two groups (t=4.721, 6.142, P<0.01). The serum VASH-1 levels in normal albuminuria group, microalbuminuria group and massive albuminuria group were (450+ 182) ng/L, (571±194) ng/L, (786±201) ng/L, and the serum TGF-β1 levels were (11.71±1.81) μg/L, (14.02±2.91) μg/L, (19.32±1.97) μg/L, respectively.Compared with the normal albuminuria group, the serum VASH-1 and TGF-β1 levels in the microalbuminuria group and the massive albuminuria group were significantly higher (P<0.05), and the serum VASH-1 and TGF-β1 levels in the massive albuminuria group were significantly higher than those in the microalbuminuria group, with significant difference between the two groups (P<0.05). Multivariate linear regression analysis showed that serum VASH-1 level was positively correlated with TGF-β1 in diabetic patients (r=0.554, P=0.000). Conclusion With the progress of DN microangiopathy, the serum VASH-1 concentration in type 2 diabetes mellitus increased significantly through negative feedback to regulate and control the formation of neovascularization and delay renal interstitial fibrosis, so as to achieve the protection of the kidney. Key words: Type 2 diabetes mellitus; Diabetic nephropathy; Angiogenesis inhibitory protein 1; Transforming growth factor β1; Urinary albumin excretion rate; Enzyme-linked immunosorbent assay

Serum vasohibin-1 and suppression of tumorigenicity-2 levels in children with predialysis chronic kidney disease

Background/aim: Chronic kidney disease (CKD), which is one of the most important health problems worldwide, could be considered as an immune inflammatory disease. A prognostic biomarker may be helpful in determining the progression of CKD in children. We aimed to investigate the serum vasohibin-1 and soluble suppression of tumorigenicity-2 (sST2) levels as potential biomarkers in children with predialysis CKD. Materials and methods: Forty-seven children with stage 2-4 CKD and 20 healthy controls were included in this cross-sectional study. Glomerular filtration rate (GFR) and urinary excretion of protein were measured in 24-h urine samples. Serum vasohibin-1 levels and sST2 were measured. The results were expressed as pg/mL and ng/mL, respectively. Results: Serum vasohibin-1 levels were similar between the patients and the control group (P > 0.05), but serum vasohibin-1 levels were higher in patients with proteinuria than in nonproteinuric patients (2574.5 ± 701.60 vs. 1822.4 ± 300.32 pg/mL, P = 0.001). A positive correlation was found between serum vasohibin-1 levels and 24-h urine protein values in patients (P = 0.036). Serum sST2 levels were higher in patients than the control group (P = 0.013). The patients with hypertension had higher sST2 levels than normotensive patients (P = 0.015). Serum vasohibin-1 and sST2 levels were not correlated with age, GFR, albumin, hemoglobin, or PTH levels. Conclusion: Serum vasohibin-1 and sST2 levels were not associated with decline in renal function. Elevated serum vasohibin levels may be a compensatory response to proteinuria in patients with predialysis CKD. The measurement of serum sST2 levels might contribute to early detection of hypertension in patients.

Expression levels of serum vasohibin-1 in type 2 diabetes mellitus patients with different excretion rates of urinary albumin and its clinical significance

Objective To investigate the expression levels of serum vasohibin-1(VASH-1)in type 2 diabetes mellitus(T2DM)patients at different stages of urinary albumin to creatinineratio(UACR)and to attempt to investigate the relationship between VASH-1 and inflammation and fibrosis in the pathogenesis of diabetic nephropathy(DN), one of the microvascular complications of T2DM. Methods 486 patients with T2DMwere divided into four groups: normal albuminuria [UACR 300 mg/g, n=106], and clinical albuminuria hypertensive [UACR>300 mg/g, with hypertension, n=124] groups. Age, course, serum levels ofVASH1, inflammation markers(CRP, ESR)and fibrosis marker(TGF-β1)with other biochemical indicators were measured, and 130 normal control subjects were also included. Results Compared with normal control group, the levels of UACR, HbA1C, ESR, CRP, TGF-β1 and VASH-1 in groups ofnormal albuminuria, microalbuminuria, clinical albuminuria, and clinical albuminuria hypertensive were significantly higher(P<0.05). Pearson correlation analysis showed that levels of VASH-1 were positively correlated with UACR, HbA1C, ESR, CRPand TGF-β1(r=0.521, 0.261, 0.519, 0.523, 0.479, P<0.001), while multivariate regression analysis showed that levels of UACR, HbA1C, ESR, CRP and TGF-β1 were important factors affecting serum VASH-1 levels. Conclusion Serum levels of VASH-1 may become new biomarkers of early diagnosis of DN. Consequently, VASH-1 level may provide a new pattern and direction of inflammation and fibrosis for consideration in diabetic kidney damage. (Chin J Endocrinol Metab, 2016, 32: 647-651) Key words: Diabetic nephrophathy; Transforming growth factor--β1; Vasohibin-1

Vasohibin-1 suppresses colon cancer.

Vasohibin-1 (VASH1) is an endogenous angiogenesis inhibitor.However, the clinical relevance of VASH1 in colon cancer and its regulations on cancer angiogenesis and cancer cell biological characteristics are still unknown. Here we showed that stromal VASH1 levels were negatively correlated with tumor size, advanced clinical stage and distant metastases in colon cancer patients. Overexpression of VASH1 in colon cancer cells induced apoptosis and senescence, inhibiting cancer cell growth and colony formation in vitro and tumor growth in vivo. In addition, knockdown of VASH1 in cancer cells promoted cell growth, adhesion and migration in vitro, and enhanced tumorigenesis and metastasis in vivo.

Expression of Vasohibin-1 in Human Carotid Atherosclerotic Plaque.

In patients with carotid plaque, intraplaque hemorrhage arising from ruptured neovascular vessels within the neointima is an important cause of stroke. The expression of Vasohibin-1 (VASH1), a negative feedback regulator of angiogenesis, occurs in the microvessel endothelial cells of various solid tumors and the arterial wall. However, the roles of VASH1 in the pathogenesis of atherosclerotic diseases remain unclear. The present study aimed to clarify the relevance of the VASH1 expression and plaque instability in human carotid plaques. We used quantitative real-time PCR and immunostaining to examine 12 atheromatous plaque specimens obtained via carotid endarterectomy. The distal areas of specimens lacking macroscopic atherosclerotic lesions served as controls. Compared with that observed in the controls, the VASH1 gene expression increased significantly in the atheromatous plaque (p=0.018). Moreover, the VASH1 mRNA levels correlated positively with those of VEGFA, CD31 and VCAM1 (r=0.788, p=0.004; r=0.99, p ＜ 0.001; r=0.94, p ＜ 0.001, respectively). Finally, the immunohistochemical analyses revealed the VASH1 expression in the neointimal microvessel endothelial cells of carotid plaque. The VASH1 expression levels in atheroma reflect both enhanced neovascularization and the inflammatory burden. Therefore, the VASH1 level may be a novel biomarker for evaluating plaque instability in patients with carotid arteriosclerosis and predicting ischemic stroke.

Urinary and plasma levels of vasohibin-1 can predict renal functional deterioration in patients with renal disorders.

Vasohibin-1 (VASH-1) is a negative feedback regulator of angiogenesis, and a small vasohibin-binding protein (SVBP) serves as its secretory chaperone and contributes to its antiangiogenic effects. In the present study, we aimed to define the clinical significance of VASH-1 and SVBP in patients with chronic kidney disease (CKD). We recruited 67 Japanese hospitalized patients with renal disorders with (n = 45) or without (n = 22) renal biopsy samples and 10 Japanese healthy controls. We evaluated the correlations between the plasma and urinary levels of VASH-1/VASH-1-SVBP complex/SVBP and the clinicopathological parameters. The plasma levels of VASH-1 were inversely correlated with age and systolic and diastolic blood pressure and positively correlated with crescent formation. Increased plasma and urinary levels of VASH-1 and VASH-1-SVBP complex were significantly correlated with worse renal outcomes. These results demonstrate an association between elevated urinary and plasma levels of VASH-1 and progressive decline of the renal function, thus suggesting a potential role for VASH-1 in predicting a worse renal prognosis in patients with renal disease, including CKD.

Renal distribution of Vasohibin-1 in patients with chronic kidney disease.

Experimental studies have demonstrated the involvement of angiogenesis-related factors in the progression of chronic kidney disease (CKD). There have so far been no reports investigating the distribution and clinical roles of Vasohibin-1 (VASH-1), a negative feedback regulator of angiogenesis, in CKD. We recruited 54 Japanese CKD patients and 6 patients who had normal renal tissues excised due to localized renal cell carcinoma. We evaluated the correlations between the renal expression level of VASH-1 and the clinical/histological parameters. VASH-1 was observed in renal endothelial/mesangial cells, crescentic lesions and interstitial inflammatory cells. Significant positive correlations were observed between 1) crescent formation and the number of VASH-1+ cells in the glomerulus (r＝0.48, p＝0.001) or cortex (r＝0.64, p＜0.0001), 2) interstitial cell infiltration and the number of VASH-1+ cells in the cortex (r＝0.34, p＝0.02), 3) the glomerular VEGFR-2+ area and the number of VASH-1+ cells in the glomerulus (r＝0.44, p＝0.01) or medulla (r＝0.63, p＝0.01). These results suggest that the renal levels of VASH-1 may be affected by local inflammation, crescentic lesions and VEGFR-2.

Suppression of Choroidal Neovascularization by Vasohibin-1, a Vascular Endothelium–Derived Angiogenic Inhibitor

PURPOSE. To determine the expression of vasohibin-1 during the development of experimentally induced choroidal neovascularization (CNV) and to investigate the effect of vasohibin-1 on the generation of CNV. METHODS. CNV lesions were induced in the eyes of wild-type (WT) and vasohibin-1 knockout (KO) mice by laser photocoagulation. The expression of vasohibin-1, vascular endothelial growth factor (VEGF), VEGF receptor-1 (VEGFR1), VEGFR2, and pigment epithelial-derived factor (PEDF) was determined by semiquantitative reverse transcription-polymerase chain reaction. The expression of vasohibin-1 was also examined by immunohistochemistry with anti-CD68, anti-alpha smooth muscle actin (αSMA), anti-cytokeratin, and anti-CD31. Vasohibin-1 was injected into the vitreous and the activity and size of the CNV were determined by fluorescein angiography and in choroidal flat mounts. RESULTS. Vasohibin-1 was detected not only in CD31-positive endothelial cells but also in CD68-positive macrophages and αSMA-positive retinal pigment epithelial cells. Strong vasohibin-1 expression was observed at day 28, when the CNV lesions had regressed by histologic examination. The vasohibin-1 level was significantly decreased at day 14 and increased at day 28 after laser application. Significantly less VEGFR2 expression was observed on day 4 after vasohibin-1. The expression of PEDF was not significantly changed by vasohibin-1 injection. Vasohibin-1 injection significantly suppressed the CNV, with no adverse side effects. The CNV lesions in the vasohibin-1-KO mice were significantly larger than those in the WT mice. CONCLUSIONS. The endogenous expression of vasohibin-1 is associated with the natural course of the development of CNV. Intravitreal injections of vasohibin-1 may be a method for inhibiting CNV.

Striated muscle angio-adaptation requires changes in Vasohibin-1 expression pattern

Vasohibin-1 (VASH-1) was recently identified as a negative feedback regulator of angiogenesis. Here, we analyzed how the expression of the two active anti-angiogenic VASH-1 isoforms p36 and p42 was altered during physiological and pathological muscle angio-adaptation. Our results showed that VASH-1 protein expression was muscle-type specific, with higher levels detected in less vascularized muscles. In rat plantaris and heart muscles, the expression of VASH-1 protein was decreased in response to exercise training, a physiological pro-angiogenic stimulus leading to muscle capillary growth. Interestingly, expression patterns for p36 and p42 were different between plantaris and heart muscles. Next, we analyzed the time-course expression of VASH-1 isoforms in rat soleus muscles subjected to hindlimb unloading, a model that induces muscle capillary regression. Both p36 and p42 isoforms were increased, a signal in favor of some vessel destabilization and regression. Finally, we investigated VASH-1 expression in plantaris muscles from Zucker Diabetic Fatty rats (ZDF) that develop obesity and type-2 diabetes associated with a loss of capillaries in skeletal muscle. VASH-1 expression was higher in sedentary ZDF rats when compared to lean animals, suggesting its potential role during capillary regression. Interestingly, a physiological VASH-1 level was efficiently restored in spontaneously active ZDF animals where muscle capillarization was preserved. In conclusion, our results bring evidence that endogenous VASH-1 isoforms p36 and p42 are key actors of physiological and pathological muscle angio-adaptation.

Vasohibin-1, a Negative Feedback Regulator of Angiogenesis, Ameliorates Renal Alterations in a Mouse Model of Diabetic Nephropathy

OBJECTIVEThe involvement of proangiogenic factors such as vascular endothelial growth factor as well as the therapeutic efficacy of angiogenesis inhibitors in early diabetic nephropathy has been reported. Vasohibin-1 (VASH-1) is a unique endogenous angiogenesis inhibitor that is induced in endothelial cells by proangiogenic factors. We investigated the therapeutic efficacy of VASH-1 in an early diabetic nephropathy model.RESEARCH DESIGN AND METHODSStreptozotocin- induced type 1 diabetic mice received intravenous injections of adenoviral vectors encoding VASH-1 (AdhVASH-1) or β-gal (AdLacZ) every other week and were killed after 28 days.RESULTSTreatment with AdhVASH-1 resulted in sustained increase in the protein levels of VASH-1 in the liver and sera, in the absence of any inflammatory alterations. AdhVASH-1 treatment significantly suppressed renal hypertrophy, glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase of the CD31+ glomerular endothelial area, F4/80+ monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix compared with AdLacZ-treated diabetic mice. Increase in the renal levels of transforming growth factor-β1, monocyte chemoattractant protein-1, and receptor for advanced glycation end products in diabetic animals was significantly suppressed by AdhVASH-1 (real-time PCR and immunoblot). VASH-1 significantly suppressed the increase of transforming growth factor-β, monocyte chemoattractant protein-1, and receptor for advanced glycation end products, induced by high ambient glucose in cultured mouse mesangial cells. Increased phosphorylation of VEGFR2 was suppressed in AdVASH-1–treated diabetic animals and in cultured glomerular endothelial cells. Endogenous mouse VASH-1 was localized to the mesangial and endothelial area in glomeruli of diabetic mice.CONCLUSIONSThese results suggest the potential therapeutic efficacy of VASH-1 in treating early diabetic nephropathy potentially mediated via glomerular endothelial and mesangial cells.