Vasohibin-1 Expression 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.

Preventive effects of vasohibin-2-targeting peptide vaccine for diabetic nephropathy.

Diabetic nephropathy remains the leading cause of end-stage kidney disease in many countries, and additional therapeutic targets are needed to prevent its development and progression. Some angiogenic factors are involved in the pathogenesis of diabetic nephropathy. Vasohibin-2 (VASH2) is a novel proangiogenic factor, and our previous study showed that glomerular damage is inhibited in diabetic Vash2 homozygous knockout mice. Therefore, we established a VASH2-targeting peptide vaccine as a tool for anti-VASH2 therapy in diabetic nephropathy. In this study, the preventive effects of the VASH2-targeting peptide vaccine against glomerular injury were examined in a streptozotocin (STZ)-induced diabetic mouse model. The mice were subcutaneously injected with the vaccine at two doses 2 wk apart and then intraperitoneally injected with 50 mg/kg STZ for 5 consecutive days. Glomerular injury was evaluated 20 wk after the first vaccination. Treatment with the VASH2-targeting peptide vaccine successfully induced circulating anti-VASH2 antibody without inflammation in major organs. Although the vaccination did not affect blood glucose levels, it significantly prevented hyperglycemia-induced increases in urinary albumin excretion and glomerular volume. The vaccination did not affect increased VASH2 expression but significantly inhibited renal angiopoietin-2 (Angpt2) expression in the diabetic mice. Furthermore, it significantly prevented glomerular macrophage infiltration. The preventive effects of vaccination on glomerular injury were also confirmed in db/db mice. Taken together, the results of this study suggest that the VASH2-targeting peptide vaccine may prevent diabetic glomerular injury in mice by inhibiting Angpt2-mediated microinflammation.NEW & NOTEWORTHY This study demonstrated preventive effects of VASH2-targeting peptide vaccine therapy on albuminuria and glomerular microinflammation in STZ-induced diabetic mouse model by inhibiting renal Angpt2 expression. The vaccination was also effective in db/db mice. The results highlight the importance of VASH2 in the pathogenesis of early-stage diabetic nephropathy and the practicability of anti-VASH2 strategy as a vaccine therapy.

Vasohibin-1 Expression Can Predict Pathological Complete Remission of Advanced Bladder Cancer with Neoadjuvant Chemotherapy.

Neoadjuvant chemotherapy (NAC) is a well-established standard practice in invasive bladder cancer (BCa), however patient selection remains challenging. High expression of vasohibin-1 (VASH1), an endogenous regulator of angiogenesis, has been reported in high-grade and advanced BCa; however, its prognostic value for chemotherapy outcomes remains unexplored. In this study, we sought to identify biomarkers of chemotherapy response focusing on the relationship between angiogenesis and tissue hypoxia. Forty Japanese patients with BCa who underwent NAC and radical cystectomy were included in the present analysis. We compared the immunohistochemical expression of CD34, VASH1, and carbonic anhydrase 9 (CA9) between patients who achieved tumor clearance at operation (ypT0) and those with residual disease after cystectomy. There were 19 patients in the ypT0 group, while the remaining 21 patients had residual tumors at operation. Patients in the ypT0 group had high microvessel density (p=0.031), high VASH1 density (p<0.001), and stronger CA9 staining (p=0.046) than their counterparts. Multivariate analysis identified microvessel and VASH1 density as independent predictive factors for pathological ypT0 disease (p=0.043 and 0.002, respectively). The 5-year recurrence-free survival rate was higher in the high VASH1 density group than in the low VASH1 density group (66.3% vs. 33.3%, p=0.036). VASH1 density is a potential therapeutic biomarker for chemotherapy response in BCa.

High Vasohibin-2 expression correlated with autophagy in proliferative diabetic retinopathy

Vasohibin-2 (VASH2) is confirmed to be associated with angiogenesis. To investigate the vitreous levels of VASH2 and how VASH2 induces angiogenesis in proliferative diabetic retinopathy (PDR), a total of 120 eyes were enrolled in this prospective and randomized controlled study and the vitreous level of VASH2 was quantified by Luminex liquid suspension chip. Vector systems were applied in human retinal microvascular endothelial cells (HRMECs) for VASH2 gene overexpression, along with interfering lentiviral vectors (VASH2-shRNA) for VASH2 gene silencing. Cell migration, autophagic flux, as well as the expression of α-tubulin, detyrosinated ⍺-tubulin, LC3 II/LC3 I, P62 were detected under normal, VASH2 overexpression, or interference conditions. The level of VASH2 in PDR patients was significantly higher (218.61 ± 30.14 pg/ml) than that in ERM/MH patients (80.78 ± 2.05 pg/ml) (P = 0.001). The migration ability of HRMECs was significantly increased in VASH2 overexpression group, while in the interfering group, the migration ability decreased. VASH2 increased the detyrosination of ⍺-tubulin. The high fluorescence intensity of autophagic flux showed an activation of autophagy in VASH2 overexpression group, which was also confirmed by the increase of LC3 II/LC3 I ratio and the decrease of P62. Collectively, the present study shows in PDR, vitreous level of VASH2 is higher. VASH2 promotes neovascularization by inducing autophagy, suggesting VASH2 could be a new anti-angiogenic drug target for PDR.

Revealing the inhibitory effect of VASH1 on ovarian cancer from multiple perspectives

ABSTRACT The function of Vasohibin-1 (VASH1) in human cancer has not been thoroughly or comprehensively examined. Here, we identified the tumor suppressor part of VASH1 across cancers, including epithelial ovarian tumors. Our study carefully contrasted the expression of VASH1 in pancancer and nontumorous tissues in a public database to explore its regulatory role in clinical prognosis, diagnosis, tumor purity, and immune cell infiltration. Next, we explored the antitumor mechanism of VASH1 through drug sensitivity, functional enrichment, and phenotypic experiments in ovarian cancer. Research suggests that the expression of VASH1 in neoplastic tissues is lower than that in normal tissues. VASH1 affects the OS and RFS of several tumor types. In addition, VASH1 expression resulted in a high OS and RFS in the diagnosis of tumor and nontumor tissues and negatively regulated tumor purity. Moreover, VASH1 controls the tumor microenvironment by regulating immunocyte infiltration. In ovarian cancer, VASH1 can serve as a biomarker to estimate the efficacy of chemotherapy. Functional enrichment analysis suggests that VASH1 plays a tumor suppressor role by regulating the extracellular matrix receptor pathway. VASH1 inhibition of the malignant phenotype of ovarian cancer cells was further confirmed by in vivo experiments. These results indicate that VASH1 acts as a cancer-inhibiting factor and potential therapeutic target in ovarian cancer.

277P Vasohibin-1 expression as a biomarker of aggressive growth in prostate ductal adenocarcinoma

277P Vasohibin-1 expression as a biomarker of aggressive growth in prostate ductal adenocarcinoma

Tregs are involved in VEGFA/ VASH1-related angiogenesis pathway in ovarian cancer

Vasohibin1 (VASH1) is a kind of vasopressor, produced by negative feedback from vascular endothelial growth factor A (VEGFA). Anti-angiogenic therapy targeting VEGFA is currently the first-line treatment for advanced ovarian cancer (OC), but there are still many adverse effects. Regulatory T cells (Tregs) are the main lymphocytes mediating immune escape function in the tumor microenvironment (TME) and have been reported to influence the function of VEGFA. However, whether Tregs are associated with VASH1 and angiogenesis in TME in OC is unclear. We aimed to explore the relationship between angiogenesis and immunosuppression in the TME of OC. We validated the relationship between VEGFA, VASH1, and angiogenesis in ovarian cancer and their prognostic implications. The infiltration level of Tregs and its marker forkhead box protein 3 (FOXP3) were explored in relation to angiogenesis-related molecules. The results showed that VEGFA and VASH1 were associated with clinicopathological stage, microvessel density and poor prognosis of ovarian cancer. Both VEGFA and VASH1 expression were associated with angiogenic pathways and there was a positive correlation between VEGFA and VASH1 expression. Tregs correlated with angiogenesis-related molecules and indicated that high FOXP3 expression is harmful to the prognosis. Gene set enrichment analysis (GSEA) predicted that angiogenesis, IL6/JAK/STAT3 signaling, PI3K/AKT/mTOR signaling, TGF-β signaling, and TNF-α signaling via NF-κB may be common pathways for VEGFA, VASH1, and Tregs to be involved in the development of OC. These findings suggest that Tregs may be involved in the regulation of tumor angiogenesis through VEGFA and VASH1, providing new ideas for synergistic anti-angiogenic therapy and immunotherapy in OC.

Altered Posttranslational Modification of Microtubules Contributes to Disturbed Enterocyte Morphology in Celiac Disease.

Celiac disease (CD) represents a frequent autoimmune disease triggered by the ingestion of gliadin in genetically predisposed individuals. The alteration of enterocytes and brush border membrane morphology have been repetitively demonstrated, but the underlying mechanisms remain unclear. Microtubules represent a major element of the cytoskeleton and exert multiple functions depending on their tyrosination status. The aim of our study was to investigate whether posttranslational modification of microtubules was altered in the context of CD and whether this mechanism contributed to morphological changes of CD enterocytes. We examined the expression of tubulin tyrosine ligase (TTL) and vasohibin-2 (VASH2) and the level of detyrosinated and acetylated tubulin in duodenal biopsies and Caco-2 cells by immunoblot and immunofluorescence microcopy. Electron microscopy was performed to investigate the subcellular distribution of detyrosinated tubulin and brush border membrane architecture in CD biopsies and Madin-Darby Canine Kidney type II (MDCK) cells lacking TTL. CD enterocytes and Caco-2 cells stimulated with digested gliadin or IFN-y displayed a flattened cell morphology. This disturbed cellular architecture was accompanied by an increased amount of detyrosinated and acetylated tubulin and corresponding high expression of VASH2 and low expression of TTL. The altered posttranslational modification of tubulin was reversible after the introduction of the gluten-free diet. CD enterocytes and MDCK cells deficient in TTL displayed a reduced cell height along with an increased cell width and a reduced number of apical microvilli. Our results provide a functional explanation for the observed morphological alterations of the enterocytes observed in CD and provide diagnostic potential of the tyrosination status of microtubules as an early marker of villous atrophy and CD inflammation.

Vasohibin-1 promotes osteoclast differentiation in periodontal disease by stimulating the expression of RANKL in gingival fibroblasts

Vasohibin-1 (VASH1) is a key inhibitor of vascular endothelial growth factor-induced angiogenesis. Although the involvement of VASH1 in various pathological processes has been extensively studied, its role in periodontal disease (PD) remains unclear. We aimed to investigate the role of VASH1 in PD by focusing on osteoclastogenesis regulation. We investigated VASH1 expression in PD by analyzing data from the online Gene Expression Omnibus (GEO) database and using a mouse ligature-induced periodontitis model. The effects of VASH1 on osteoclast differentiation and osteoclastogenesis-supporting cells were assessed in mouse bone marrow-derived macrophages (BMMs) and human gingival fibroblasts (GFs). To identify the stimulant of VASH1, we used culture broth from Porphyromonas gingivalis (Pg), a periopathogen. The GEO database and mouse periodontitis model revealed that VASH1 expression was upregulated in periodontitis-affected gingival tissues, which was further supported by immunohistochemistry and qRT-PCR analyses. VASH1 expression was significantly stimulated in GFs after treatment with the Pg broth. Direct treatment with recombinant VASH1 protein did not stimulate osteoclast differentiation in BMMs but did contribute to osteoclast differentiation by inducing RANKL expression in GFs through a paracrine mechanism. Small interfering RNA-mediated silencing of VASH1 in GFs abrogated RANKL-mediated osteoclast differentiation in BMMs. Additionally, VASH1-activated RANKL expression in GFs was significantly suppressed by MK-2206, a selective inhibitor of AKT. These results suggest that Pg-induced VASH1 may be associated with RANKL expression in GFs in a paracrine manner, contributing to osteoclastogenesis via an AKT-dependent mechanism during PD progression.

Vasohibin-2 promotes proliferation and metastasis of cervical cancer cells by regulating epithelial-mesenchymal transition

To explore the role of vasohibin-2 (VASH2) in regulation of proliferation and metastasis of cervical cancer cells. We analyzed the differentially expressed genes between cervical cancer cells with flotillin-1 overexpression and knockdown by RNA-seq combined with analysis of public databases. The expression levels of VASH2 were examined in normal cervical epithelial cells (HcerEpic), cervical cancer cell lines (HeLa, C-33A, Ca ski, SiHa and MS751) and fresh cervical cancer tissues with different lymph node metastasis status. We further tested the effects of lentivirus-mediated overexpression and interference of VASH2 on proliferation, migration, invasion and lymphatic vessel formation of the cervical cancer cells and detected the expression levels of key epithelial-mesenchymal transition (EMT) markers and TGF-β mRNA. RNA-seq and analysis of public databases showed that VASH2 expression was significantly upregulated in cervical cancer cells exogenously overexpressing flotillin-1 (P < 0.05) and downregulated in cells with flotillin-1 knockdown (P < 0.05), and was significantly higher in cervical cancer tissues with lymph node metastasis than in those without lymph node metastasis (P < 0.01). In cervical cancer cell lines Ca Ski, SiHa, and MS751 and cervical cancer tissue specimens with lymph node metastasis, VASH2 expression was also significantly upregulated as compared with HcerEpic cells and cervical cancer tissues without lymph node metastasis (P < 0.05). Exogenous overexpression of VASH2 significantly promoted proliferation, migration, invasion and lymphatic vessel formation of cervical cancer cells, whereas these abilities were significantly inhibited in cells with VASH2 knockdown (P < 0.05). The cervical cancer cells overexpressing VASH2 showed significant down- regulation of e-cadherin and up- regulation of N-cadherin, Vimentin and VEGF-C, while the reverse changes were detected in cells with VASH2 knockdown (P < 0.05). TGF-β mRNA expression was significantly up-regulated in cervical cancer cells overexpressing VASH2 and down-regulated in cells with VASH2 knockdown (P < 0.001). Flotillin-1 may participate in TGF-β signaling pathway-mediated EMT through its down-stream target gene VASH2 to promote the proliferation, migration, invasion and lymphatic vessel formation of cervical cancer cells in vitro.

Significance of vasohibin 1 in cancer patients: A systematic review and meta analysis.

This study analyzed the role of vasohibin-1 (VASH1) in human cancer outcomes. Relevant original studies on VASH1 expression in cancers were searched from PubMed, ClinicalKey, and Cochrane Library databases. A meta-analysis was performed to evaluate the role of VASH1 in clinicopathological characteristics and overall survival (OS) of patients with tumors. Statistical analysis was performed using the RevMan v. 5.3 software. Our meta-analysis results showed that patients with high VASH1 expression experienced a significantly poor prognosis with a hazard ratio (HR) of 1.69 (95% confidence interval [CI], 1.16- 2.46, P = 0.006) for OS, and an HR of 2.21 (95% CI, 1.32-3.68, P = 0.003) for progression-free survival. Furthermore, the high expression of VASH1 was significantly relevant to advanced tumor node metastasis stages. Thus, VASH1 is a potential biomarker to predict unfavorable clinical outcomes, serving as a potential tumor treatment target.

Vasohibin-1 has α-tubulin detyrosinating activity in glomerular podocytes

Podocytes are highly specialized epithelial cells in glomeruli, with a complex morphology composed of a cell body, primary processes, and foot processes, which maintain barrier function in glomerular filtration. The microtubule-based cytoskeleton is necessary for podocyte morphology. Microtubule structure and function can be affected by post-translational modification of tubulin, including detyrosination. Recent studies have shown that vasohibin-1 (VASH1), an antiangiogenic factor, has tubulin carboxypeptidase activity that causes detyrosination of α-tubulin. We aimed to examine the role of VASH1 in regulating α-tubulin detyrosination in podocytes and the potential involvement of VASH1 deficiency in renal morphology. In normal mouse kidneys, detyrosinated α-tubulin was mainly identified in glomeruli, especially in podocytes; meanwhile, in cultured immortalized podocytes, α-tubulin detyrosination was promoted with cell differentiation. Notably, α-tubulin detyrosination in glomeruli was diminished in Vash1 homozygous knockout (Vash1−/−) mice, and knockdown of VASH1 in cultured podocytes prevented α-tubulin detyrosination. Although VASH1 deficiency-induced downregulation of detyrosination caused no remarkable glomerular lesions, urinary albuminuria excretion and glomerular volume were significantly higher in Vash1−/− mice than in wild-type mice. Furthermore, decreased glomerular nephrin expression and narrower slit diaphragms width were observed in Vash1−/− mice. Taken together, we demonstrated that α-tubulin detyrosination in podocytes was mainly regulated by VASH1 and that VASH1 deficiency-mediated decreases in α-tubulin detyrosination led to minor alterations in podocyte morphology and predisposition to albuminuria. VASH1 expression and α-tubulin detyrosination may be novel targets for maintaining glomerular filtration barrier integrity.

Clinicopathological Role of Vasohibin in Gastroenterological Cancers: A Meta-Analysis.

Vasohibin-1 (VASH1) is an angiogenesis inhibitor, while vasohibin-2 (VASH2) is a proangiogenic factor. The roles of VASH1 and VASH2 expression in gastroenterological cancers remain unclear. We searched for relevant literature, specifically studies on gastroenterological cancer, and evaluated the relationship between VASH expression and clinical outcomes. Nine studies on VASH1 involving 1,574 patients were included. VASH1 expression was associated with the TNM stage [OR (odds ratio) 2.05, 95% CI (confidence interval) 1.24-3.40], lymph node metastasis (OR 1.79, 95% CI 1.24-2.58), lymphatic invasion (OR 1.95, 95% CI 1.41-2.68), and venous invasion (OR 2.49, 95% CI 1.60-3.88); poor clinical outcomes were associated with high VASH1 expression. High VASH1 expression was associated with a significantly shorter overall survival (OS) [HR (hazard ratio) 1.69, 95% CI 1.25-2.29] and disease-free survival (DFS) (HR 2.01, 95% CI 1.28-3.15). Three studies on VASH2 involving 469 patients were analyzed. VASH2 expression was associated with the TNM stage (OR 4.21, 95% CI 1.89-9.51) and venous invasion (OR 2.10, 95% CI 1.15-3.84); poor clinical outcomes were associated with high VASH2 expression. High VASH2 expression was associated with a significantly lower OS (HR 1.61, 95% CI 1.09-2.37). In conclusion, high VASH1 and VASH2 expression levels were associated with poor clinical outcomes and prognosis in patients with gastroenterological cancers.

Pathological Study on the Expression of Vasohibins in Peripheral Artery Disease.

Vasohibin-2 (VASH2) is a gene that promotes local angiogenesis. The tubulin carboxypeptidase activity of vasohibin causes detyrosination of alpha-tubulin and may play an important role in the regulation of various phenomena. Pathological and therapeutic angiogenesis are involved in atherosclerotic lesions. This study aimed to investigate whether the expression of VASH2 is associated with peripheral artery disease (PAD) in relation to angiogenesis, tubulin detyrosination, and severity of atherosclerotic lesions. An analysis of femoral and tibial arteries obtained from 86 patients with PAD or abdominal aortic aneurysm (AAA) was performed. The expressions of cluster of differentiation 31, VASH1, VASH2, and detyrosinated alpha-tubulin (DT-tubulin) were examined by immunohistochemistry, and their association with PAD was analyzed. The counts of VASH2 in the tunica media and adventitia in the tibial artery were significantly higher than those in the femoral artery in the PAD (P = 0.005 and P = 0.008, respectively) and AAA (P = 0.002 and P < 0.001, respectively) groups. In the tunica media and adventitia, VASH2 was significantly correlated with DT-tubulin. There was no significant difference in the expression of VASH2 and DT-tubulin in medial smooth muscle cells (McNemar test, P > 0.999). This study revealed the possible involvements of VASH2 in atherosclerosis by two methods-one maybe related to the progression of atherosclerosis by inducing angiogenesis and the second may be related to the decrease in arterial elasticity by increasing DT-tubulin in medial smooth muscle cells.

Cardiac glycosides from Digitalis lanata and their cytotoxic activities.

Cardiac glycosides (CGs) are good candidates as drug leads in the treatment of cancer because of their structural diversities and potent biological activities. In this study, fifteen CGs including three new ones (1–3) were isolated from Digitalis lanata Ehrh. Their structures were elucidated by HRESIMS, NMR spectroscopic methods, including homonuclear and heteronuclear coupling constant analysis, and acid-catalyzed hydrolysis and derivatization analysis of the sugar chain. The cytotoxic activities of these CGs were evaluated against three human cancer cell lines (A549, HeLa and MCF-7 cell lines), and all of them showed strong activities at nanomolar scale. The flow cytometric analysis indicated that compound 1 induced cell cycle arrest in the G2/M phase. Transcriptome analysis revealed a panel of possible targets for compound 1. RT-PCR and western blot experiments showed that 1 significantly inhibited the expression of vasohibin-2 (VASH2). Moreover, compound 1 restrained angiogenesis in a concentration-dependent manner in the chick embryo chorioallantoic membrane (CAM) model.

Vasohibin-1 expression as a biomarker of aggressive nature in ductal adenocarcinoma of the prostate: a retrospective cohort study at two centres in Japan

ObjectivesVasohibin-1 (VASH1) is an endogenous angiogenesis regulator expressed in activated vascular endothelial cells. We previously reported that high VASH1 expression is a predictor of progression in acinar adenocarcinoma of the...

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 rescues erectile function through up-regulation of angiogenic factors in the diabetic mice

Neovascularization of the erectile tissue emerges as a beneficial curative approach to treat erectile dysfunction (ED). Here we for the first time report the unexpected role of vasohibin-1 (VASH1), mainly known as an anti-angiogenic factor, in restoring erectile function in diabetic mice. A diabetic patient has lower cavernous VASH1 expression than in the potent man. VASH1 was mainly expressed in endothelial cells. There were significant decreases in cavernous endothelial cell and pericyte contents in VASH1 knockout mice compared with those in wild-type mice, which resulted in impairments in erectile function. Intracavernous injection of VASH1 protein successfully restored erectile function in the diabetic mice (~ 90% of control values). VASH1 protein reinstated endothelial cells, pericytes, and endothelial cell–cell junction proteins and induced phosphorylation of eNOS (Ser1177) in the diabetic mice. The induction of angiogenic factors, such as angiopoietin-1 and vascular endothelial growth factor, is responsible for cavernous angiogenesis and the restoration of erectile function mediated by VASH1. Altogether, these findings suggest that VASH1 is proangiogenic in diabetic penis and is a new potential target for diabetic ED.

Genetic Deletion of Vasohibin-2 Exacerbates Ischemia-Reperfusion-Induced Acute Kidney Injury.

Acute kidney injury (AKI) has been increasingly recognized as a risk factor for transition to chronic kidney disease. Recent evidence suggests that endothelial damage in peritubular capillaries can accelerate the progression of renal injury. Vasohibin-2 (VASH2) is a novel proangiogenic factor that promotes tumor angiogenesis. However, the pathophysiological roles of VASH2 in kidney diseases remain unknown. In the present study, we examined the effects of VASH2 deficiency on the progression of ischemia–reperfusion (I/R) injury-induced AKI. I/R injury was induced by bilaterally clamping renal pedicles for 25 min in male wild-type (WT) and Vash2 homozygous knockout mice. Twenty-four hours later, I/R injury-induced renal dysfunction and tubular damage were more severe in VASH2-deficient mice than in WT mice, with more prominent neutrophil infiltration and peritubular capillary loss. After induction of I/R injury, VASH2 expression was markedly increased in injured renal tubules. These results suggest that VASH2 expression in renal tubular epithelial cells might be essential for alleviating I/R injury-induced AKI, probably through protecting peritubular capillaries and preventing inflammatory infiltration.

Prognostic significance of vasohibin-1 and vasohibin-2 immunohistochemical expression in gastric cancer.

It was recently identified that the vasohibin family may regulate angiogenesis through suppression by the vasohibin-1 gene and promotion by the vasohibin-2 gene. We assessed vasohibin expression in gastric cancer patients and its effect on their prognosis. We evaluated vasohibin immunohistochemical expression in 210 patients with gastric cancer, who underwent radical surgery. The patients were divided first into a vasohibin-1-positive group and a vasohibin-1-negative group, and then into groups with high or low vasohibin-2 expression, to allow us to investigate the clinicopathological factors of prognosis retrospectively. There were 139 patients in the vasohibin-1-positive group and 71 patients in the vasohibin-1-negative group, among which there were and 108 with high vasohibin-2 expression and 102 with low vasohibin-2 expression. Vasohibin-1 was associated with Ly (P = 0.003) and pT (P = 0.037), whereas vasohibin-2 was associated with Ly (P < 0.001), V (P < 0.001) and pStage (P < 0.001). Overall, cancer-specific and relapse-free survival rates were lower in the vasohibin-1-positive (P = 0.034, P < 0.001, P = 0.002, respectively) and high vasohibin-2 expression (P = 0.004, P = 0.003, P < 0.001, respectively) groups. Multivariate analysis revealed that vasohibin-1 expression was associated with cancer-specific (P = 0.014, hazard ratio [HR] 4.454) and relapse-free (P = 0.035, HR 2.557) survival and vasohibin-2 expression tended to influence relapse-free survival (P = 0.051, HR 2.061). Grouping patients by vasohibin expression status combinations showed correlation among their expressions (P = 0.005). Overall, cancer-specific and relapse-free survival rates were lowest in the vasohibin-1-positive and high vasohibin-2 expression group. Our findings demonstrate that vasohibin-1 and vasohibin-2 could be novel biomarkers for predicting gastric cancer prognosis.