scholarly journals The mechanism of long-term low-dose asymmetric dimethylarginine inducing transforming growth factor-β expression in endothelial cells

2012 ◽  
Vol 31 (1) ◽  
pp. 67-74 ◽  
Author(s):  
YIDUO FENG ◽  
DONGLIANG ZHANG ◽  
YU ZHANG ◽  
QIDONG ZHANG ◽  
WENHU LIU
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Low Dose ◽  
Asymmetric Dimethylarginine ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β

scholarly journals Chronic NOS inhibition actuates endothelial-mesenchymal transformation

2007 ◽  
Vol 292 (1) ◽  
pp. H285-H294 ◽  
Author(s):  
Edmond O’Riordan ◽  
Natalia Mendelev ◽  
Susann Patschan ◽  
Daniel Patschan ◽  
Jonathan Eskander ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Asymmetric Dimethylarginine ◽  
Transforming Growth Factor ◽  
Fluorescent Protein ◽  
Transforming Growth Factor Β ◽  
Tissue Growth ◽  
Collagen Xviii ◽  
Green Fluorescent

Chronic kidney diseases are accompanied by the accumulation of substances like asymmetric dimethylarginine, phenylacetic acid, homocysteine, and advanced glycation end products, known to either inhibit endothelial nitric oxide synthase (eNOS) or uncouple it, consequently limiting the amount of available nitric oxide (NO). Reduced bioavailability of NO induces endothelial dysfunction. An early loss of peritubular capillaries in tubulointerstitial fibrotic areas and injury to endothelial cells have been linked to progressive renal disease. Screening endothelial genes in cells treated with NOS inhibitors showed upregulation of collagen XVIII, a precursor of a potent antiangiogenic substance, endostatin. This finding was confirmed at the level of mRNA and protein expression. Tie-2 promoter-driven green fluorescent protein mice treated with nonhypertensinogenic doses of a NOS inhibitor exhibited upregulation of collagen XVIII/endostatin and rarefaction of capillary profiles. This was accompanied by the increased expression of transforming growth factor-β and connective tissue growth factor in the kidney. Occasional endothelial cells expressed both the marker of endothelial lineage (green fluorescent protein) and mesenchymal marker (α-smooth muscle actin or calponin). In vitro studies of endothelial cells treated with asymmetric dimethylarginine showed decreased expression of eNOS and Flk-1 and enhanced expression of calponin and fibronectin, additional markers of smooth muscle and mesenchymal cells. These cells overexpressed transforming growth factor-β and connective tissue growth factor, as well as endostatin. In conclusion, data presented here 1) ascribe to NO deficiency in endothelial cells the function of a profibrotic stimulus associated with the expression of an antiangiogenic fragment of collagen XVIII (endostatin) and 2) provide evidence of endothelial-mesenchymal transdifferentiation in the course of inhibition of NOS by a pathophysiologically important antagonist, asymmetric dimethylarginine. Both mechanisms may account for microvascular rarefaction.

Intracisternal administration of transforming growth factor-β evokes fever through the induction of cyclooxygenase-2 in brain endothelial cells

2008 ◽  
Vol 294 (1) ◽  
pp. R266-R275 ◽  
Author(s):  
Shigenobu Matsumura ◽  
Tetsuro Shibakusa ◽  
Teppei Fujikawa ◽  
Hiroyuki Yamada ◽  
Kiyoshi Matsumura ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Proinflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cyclooxygenase 2 ◽  
Dependent Manner ◽  
Cox 2 ◽  
Β Receptor

Transforming growth factor-β (TGF-β), a pleiotropic cytokine, regulates cell proliferation, differentiation, and apoptosis, and plays a key role in development and tissue homeostasis. TGF-β functions as an anti-inflammatory cytokine because it suppresses microglia and B-lymphocyte functions, as well as the production of proinflammatory cytokines. However, we previously demonstrated that the intracisternal administration of TGF-β induces fever like that produced by proinflammatory cytokines. In this study, we investigated the mechanism of TGF-β-induced fever. The intracisternal administration of TGF-β increased body temperature in a dose-dependent manner. Pretreatment with cyclooxygenase-2 (COX-2)-selective inhibitor significantly suppressed TGF-β-induced fever. COX-2 is known as one of the rate-limiting enzymes of the PGE2 synthesis pathway, suggesting that fever induced by TGF-β is COX-2 and PGE2 dependent. TGF-β increased PGE2 levels in cerebrospinal fluid and increased the expression of COX-2 in the brain. Double immunostaining of COX-2 and von Willebrand factor (vWF, an endothelial cell marker) revealed that COX-2-expressing cells were mainly endothelial cells. Although not all COX-2-immunoreactive cells express TGF-β receptor, some COX-2-immunoreactive cells express activin receptor-like kinase-1 (ALK-1, an endothelial cell-specific TGF-β receptor), suggesting that TGF-β directly or indirectly acts on endothelial cells to induce COX-2 expression. These findings suggest a novel function of TGF-β as a proinflammatory cytokine in the central nervous system.

Transforming Growth Factor-β: Role in Mediating Serum-Induced Endothelin Production by Vascular Endothelial Cells*

Endocrinology ◽  
1991 ◽  
Vol 129 (5) ◽  
pp. 2355-2360 ◽  
Author(s):  
MARVIN R. BROWN ◽  
JOAN VAUGHAN ◽  
LETICIA L. JIMENEZ ◽  
WYLIE VALE ◽  
ANDREW BAIRD
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Vascular Endothelial Cells ◽  
Transforming Growth Factor Β ◽  
Vascular Endothelial

Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells

2014 ◽  
Vol 66 (12) ◽  
pp. 1722-1733 ◽  
Author(s):  
Danielle Kamato ◽  
Muhamad Ashraf Rostam ◽  
Terence J. Piva ◽  
Hossein Babaahmadi Rezaei ◽  
Robel Getachew ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Vascular Endothelial Cells ◽  
Transforming Growth Factor Β ◽  
Vascular Endothelial ◽  
Site Specific ◽  
Linker Region

scholarly journals Topically Applied Etamsylate: A New Orphan Drug for HHT-Derived Epistaxis (Antiangiogenesis through FGF Pathway Inhibition)

TH Open ◽  
2019 ◽  
Vol 03 (03) ◽  
pp. e230-e243 ◽  
Author(s):  
Virginia Albiñana ◽  
Guillermo Giménez-Gallego ◽  
Angela García-Mato ◽  
Patricia Palacios ◽  
Lucia Recio-Poveda ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Orphan Drug ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Life Threatening ◽  
Vascular Dysplasia ◽  
Pathway Inhibition

AbstractHereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by recurrent and spontaneous epistaxis (nose bleeds), telangiectases on skin and mucosa, internal organ arteriovenous malformations, and dominant autosomal inheritance. Mutations in Endoglin and ACVRL1/ALK1, genes mainly expressed in endothelium, are responsible in 90% of the cases for the pathology. These genes are involved in the transforming growth factor-β(TGF-β) signaling pathway. Epistaxis remains as one of the most common symptoms impairing the quality of life of patients, becoming life-threatening in some cases. Different strategies have been used to decrease nose bleeds, among them is antiangiogenesis. The two main angiogenic pathways in endothelial cells depend on vascular endothelial growth factor and fibroblast growth factor (FGF). The present work has used etamsylate, the diethylamine salt of the 2,5-dihydroxybenzene sulfonate anion, also known as dobesilate, as a FGF signaling inhibitor. In endothelial cells, in vitro experiments show that etamsylate acts as an antiangiogenic factor, inhibiting wound healing and matrigel tubulogenesis. Moreover, etamsylate decreases phosphorylation of Akt and ERK1/2. A pilot clinical trial (EudraCT: 2016–003982–24) was performed with 12 HHT patients using a topical spray of etamsylate twice a day for 4 weeks. The epistaxis severity score (HHT-ESS) and other pertinent parameters were registered in the clinical trial. The significant reduction in the ESS scale, together with the lack of significant side effects, allowed the designation of topical etamsylate as a new orphan drug for epistaxis in HHT (EMA/OD/135/18).

Expression of human β-defensin-2 in intratumoral vascular endothelium and in endothelial cells induced by transforming growth factor β

Peptides ◽  
2010 ◽  
Vol 31 (2) ◽  
pp. 195-201 ◽  
Author(s):  
Hameem I. Kawsar ◽  
Santosh K. Ghosh ◽  
Stanley A. Hirsch ◽  
Henry B. Koon ◽  
Aaron Weinberg ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Vascular Endothelium ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β
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