Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis

Watanabe, Kazuhide; Hasegawa, Yasuhiro; Yamashita, Hiroshi; Shimizu, Kazuharu; Ding, Yuanying; Abé, Mayumi; Ohta, Hiroyuki; Imagawa, Keiichi; Hojo, Kanji; Maki, Hisae; Sonoda, Hidenori; Sato, Yasufumi

doi:10.1172/jci21152

Cited by 142 publications

(208 citation statements)

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“…We previously demonstrated that exogenous VASH1 prevents neointimal formation together with neovascularization and macrophage accumulation in the adventitia (Yamashita et al ., 2006). VASH1 is an endothelium‐derived factor with dual functions: One is inhibition of angiogenesis, and the other is promotion of stress resistance (Watanabe et al ., 2004; Miyashita et al ., 2012). We therefore speculate that the decreased stress resistance of ECs in Vash1 (−/−) mice was rather responsible for this increased macrophage accumulation in the adventitia and that it promoted the neointimal formation.…”

Section: Discussionmentioning

confidence: 99%

“…Next, the separated proteins were transferred to the membranes, which were blocked for 1 h at room temperature with Tris–HCl‐buffered saline (TaKaRa Bio, Shiga, Japan) containing 0.05% Tween‐20 (T‐TBS) and 2.5% skim milk. After the transfer, the membranes were incubated for 1 h at room temperature with HRP‐conjugated anti‐human VASH1 mAb (4E12, 1:1000 dilution; Watanabe et al ., 2004), anti‐human β‐actin monoclonal antibody (1:10000; Sigma‐Aldrich), or anti‐human α‐tubulin monoclonal antibody (1:1000 dilution; Merck Millipore, Billerica, MA, USA). After the membranes had been washed 3 times with T‐TBS, they were incubated for 1 h at room temperature with anti‐rat IgG (whole molecule)‐peroxidase antibody or anti‐mouse IgG (whole molecule)‐peroxidase antibody (Sigma‐Aldrich) as a secondary antibody.…”

Section: Methodsmentioning

confidence: 99%

“…We recently isolated vasohibin‐1 (VASH1) as a factor synthesized by ECs that inhibits angiogenesis in an auto‐regulatory manner (Watanabe et al ., 2004). Our recent analysis revealed that VASH1 has an additional function of increasing stress resistance of ECs by increasing the expression of superoxide dismutase 2 (SOD2) and sirtuin 1 (SIRT1; Miyashita et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

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Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

2016

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SummaryVasohibin‐1 (VASH1) is an angiogenesis‐inhibiting factor synthesized by endothelial cells (ECs) and it also functions to increase stress tolerance of ECs, which function is critical for the maintenance of vascular integrity. Here, we examined whether the expression of VASH1 would be affected by aging. We passaged human umbilical vein endothelial cells (HUVECs) and observed that VASH1 was downregulated in old HUVECs. This decrease in VASH1 expression with aging was confirmed in mice. To explore the mechanism of this downregulation, we compared the expression of microRNAs between old and young HUVECs by performing microarray analysis. Among the top 20 microRNAs that were expressed at a higher level in old HUVECs, the third highest microRNA, namely miR‐22‐3p, had its binding site on the 3′ UTR of VASH1 mRNA. Experiments with microRNA mimic and anti‐miR revealed that miR‐22‐3p was involved at least in part in the downregulation of VASH1 in ECs during replicative senescence. We then clarified the significance of this defective expression of VASH1 in the vasculature. When a cuff was placed around the femoral arteries of wild‐type mice and VASH1‐null mice, neointimal formation was augmented in the VASH1‐null mice accompanied by an increase in adventitial angiogenesis, macrophage accumulation in the adventitia, and medial/neointimal proliferating cells. These results indicate that in replicative senescence, the downregulation of VASH1 expression in ECs was caused, at least in part, by the alteration of microRNA expression. Such downregulation of VASH1 might be involved in the acceleration of age‐associated vascular diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

2016

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“…VASH1 is predominantly expressed on endothelial cells based on the immunohistochemistry data in humans and mice. Recombinant VASH1 inhibits endothelial cell migration, proliferation, and network formation in vitro as well as angiogenesis in vivo (Watanabe et al 2004, Hosaka et al 2009, Heishi et al 2010. Furthermore, the coadministration of VASH1 with VEGFA has been reported to block, almost completely, not only VEGFA-induced angiogenesis but also lymphangiogenesis in the mouse cornea (Heishi et al 2010).…”

Section: Introductionmentioning

confidence: 99%

“…However, little is known about endogenous inhibitors of angiogenesis in the bovine CL. Watanabe et al (2004) recently discovered a novel endothelium-derived negative feedback regulator of angiogenesis, vasohibin-1 (VASH1), by searching for VEGFA-inducible genes in human endothelial cells using DNA microarray analysis and isolating the previously uncharacterized gene VASH1. Human VASH1 protein is composed of 365 amino acid residues, with no detectable glycosylation.…”

Section: Introductionmentioning

confidence: 99%

Possible action of vasohibin-1 as an inhibitor in the regulation of vascularization of the bovine corpus luteum

et al. 2012

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The development of the corpus luteum (CL), which secretes large amounts of progesterone to establish pregnancy, is accompanied by active angiogenesis, vascularization, and lymphangiogenesis. Negative feedback regulation is a critical physiological mechanism. Vasohibin-1 (VASH1) was recently discovered as a novel endothelium-derived negative feedback regulator of vascularization. We therefore investigated the expression of VASH1 in the bovine CL. Expression of VASH1 mRNA and protein was predominantly localized to luteal endothelial cells (LECs). VASH1 expression in the CL was constant through the early to late luteal phases and decreased during CL regression relating with the action of luteolytic prostaglandin F 2a in vivo. To investigate the role of VASH1, we determined whether VASH1 treatment affects angiogenesis and/or lymphangiogenesis using LECs and lymphatic endothelial cells (LyECs) in vitro. Vascular endothelial growth factor A (VEGFA) stimulated the expression of VASH1 in LECs but not in LyECs, and VASH1 completely blocked VEGFA-induced formation of capillary-like tube structures of LECs and LyECs in vitro. In summary, VASH1 is predominantly located on LECs in the bovine CL and inhibits the angiogenic and lymphangiogenic actions of VEGFA. Bovine CL therefore has a VEGFA-VASH1 system that may be involved in regulation of luteal function, especially in the development of the CL. The results indicate that VASH1 has the potential to act as a negative feedback regulator of angiogenesis and lymphangiogenesis in the CL in cows.

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Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats

Richter¹,

Natura²,

Löser³

et al. 2010

Arthritis & Rheumatism

106

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Objective. During inflammation in the joint, normal joint movements are usually painful. A neuronal mechanism for this form of mechanical hyperalgesia is the persistent sensitization of joint nociceptors to mechanical stimuli. Because tumor necrosis factor (TNF) is a major mediator of joint inflammation, we undertook the present study both to explore the potential of TNF to sensitize joint nociceptors to mechanical stimuli and to address the cellular mechanism involved.Methods. In anesthetized rats, action potentials (APs) were recorded from sensory nociceptive A␦ fibers and C fibers supplying the knee joint. We monitored responses to rotation of the knee joint at innocuous and noxious intensities. TNF, etanercept, and a p38 inhibitor were injected into the knee joint, and the cyclooxygenase (COX) inhibitor diclofenac was administered intraperitoneally. APs were also recorded in isolated cultured dorsal root ganglion (DRG) neurons in order to test for changes in neuronal excitability induced by TNF.Results. A single application of TNF into the normal knee joint caused a significant persistent sensitization of nociceptive sensory fibers to mechanical stimuli applied to the joint. This effect was dose dependent. It was prevented by coadministration of etanercept or by an inhibitor of p38, and it was attenuated by systemic application of a COX inhibitor. Patch clamp recordings from isolated DRG neurons showed a rapid increase in neuronal excitability induced by TNF.Conclusion. TNF can induce a long-lasting sensitization of joint nociceptors to mechanical stimuli and thus can induce long-lasting mechanical hyperalgesia in joints. TNF can act directly on neurons, underscoring its role as a sensitizing pain mediator.

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Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis

Cited by 142 publications

References 36 publications

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

Possible action of vasohibin-1 as an inhibitor in the regulation of vascularization of the bovine corpus luteum

Tumor necrosis factor causes persistent sensitization of joint nociceptors to mechanical stimuli in rats

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