Transforming growth factor-β1 downregulates caveolin-1 expression and enhances sphingosine 1-phosphate signaling in cultured vascular endothelial cells

2009 ◽  
Vol 297 (5) ◽  
pp. C1263-C1274 ◽  
Author(s):  
Junsuke Igarashi ◽  
Kazuyo Shoji ◽  
Takeshi Hashimoto ◽  
Tetsuya Moriue ◽  
Kozo Yoneda ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Vascular Endothelial Cells ◽  
Transforming Growth Factor Β1 ◽  
Receptor Subtype ◽  
Receptor Signaling ◽  
Caveolin 1 ◽  
Alk 5 ◽  
Tgf Β1

In vascular endothelial cells, specialized microdomains of plasma membrane termed caveolae modulate various receptor signal transduction pathways regulated by caveolin-1, a resident protein of caveolae. We examined whether transforming growth factor-β1 (TGF-β1), a multifunctional cytokine, alters expression levels of caveolin-1 and influences heterologous receptor signaling. Treatment of cultured bovine aortic endothelial cells (BAEC) with TGF-β1 induces marked decreases in caveolin-1 expression in a time- and dose-dependent fashion at both levels of protein and mRNA. A pharmacological inhibitor of activin receptor-like kinase 5 (ALK-5) counteracts caveolin-1 downregulation by TGF-β1, indicating the involvement of ALK-5 receptor subtype for TGF-β1. Sphingosine 1-phosphate (S1P) is a serum-borne angiogenic lipid growth factor that exerts a wide variety of biological actions. S1P modulates G protein-coupled S1P receptors, activating downstream molecules kinases AMP-activated protein kinase (AMPK), and Akt as well as a small G protein Rac1, ultimately to promote migration. Because S1P receptor signaling is associated with caveolae/caveolin-1, we examined whether pretreatment with TGF-β1 enhances effects of S1P on BAEC. Whereas S1P alone evokes robust BAEC responses to S1P, pretreatment with TGF-β1 leads to even higher magnitudes of S1P-elicited signaling responses and cell migration. Conversely, genetic knockdown of caveolin-1 using small interfering RNA mimics TGF-β1-induced promotion of BAEC responses to S1P. Collectively, these data demonstrate that TGF-β1 downregulates caveolin-1 of cultured endothelial cells, involving ALK-5 receptor subtype. Because downregulation of caveolin-1 by TGF-β1 promotes subsequent heterologous receptor signaling by S1P, these results may also identify novel point of cross-talk between cytokines and sphingolipids within endothelial signal transduction machineries.

scholarly journals Transforming Growth Factor β1 (TGF-β1) Promotes Endothelial Cell Survival during In Vitro Angiogenesis via an Autocrine Mechanism Implicating TGF-α Signaling

2001 ◽  
Vol 21 (21) ◽  
pp. 7218-7230 ◽  
Author(s):  
Francesc Viñals ◽  
Jacques Pouysségur
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Cell Survival ◽  
Network Formation ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
In Vitro Angiogenesis ◽  
Tgf Β1

ABSTRACT Mouse capillary endothelial cells (1G11 cell line) embedded in type I collagen gels undergo in vitro angiogenesis. Cells rapidly reorganize and form capillary-like structures when stimulated with serum. Transforming growth factor β1 (TGF-β1) alone can substitute for serum and induce cell survival and tubular network formation. This TGF-β1-mediated angiogenic activity depends on phosphatidylinositol 3-kinase (PI3K) and p42/p44 mitogen-activated protein kinase (MAPK) signaling. We showed that specific inhibitors of either pathway (wortmannin, LY-294002, and PD-98059) all suppressed TGF-β1-induced angiogenesis mainly by compromising cell survival. We established that TGF-β1 stimulated the expression of TGF-α mRNA and protein, the tyrosine phosphorylation of a 170-kDa membrane protein representing the epidermal growth factor (EGF) receptor, and the delayed activation of PI3K/Akt and p42/p44 MAPK. Moreover, we showed that all these TGF-β1-mediated signaling events, including tubular network formation, were suppressed by incubating TGF-β1-stimulated endothelial cells with a soluble form of an EGF receptor (ErbB-1) or tyrphostin AG1478, a specific blocker of EGF receptor tyrosine kinase. Finally, addition of TGF-α alone poorly stimulated angiogenesis; however, by reducing cell death, it strongly potentiated the action of TGF-β1. We therefore propose that TGF-β1 promotes angiogenesis at least in part via the autocrine secretion of TGF-α, a cell survival growth factor, activating PI3K/Akt and p42/p44 MAPK.

scholarly journals Transforming Growth Factor- β1 Signaling in Vascular Endothelial Cells Inhibits Hematopoietic Stem Cell Regeneration

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1493-1493
Author(s):  
Derek Zachman ◽  
Devorah C Goldman ◽  
Chandan Guha ◽  
Beth Wilmot ◽  
William H. Fleming
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Conflicts Of Interest ◽  
Umbilical Vein ◽  
Transforming Growth Factor Β1 ◽  
Dependent Manner ◽  
Hematopoietic Stem ◽  
Tgf Β1

Abstract Endothelial cells (EC) are known to be essential for hematopoietic regeneration; however, little is known about the pathways that regulate this activity. By modeling endothelial-dependent HSC interactions in vitro, we found that human umbilical vein endothelial cells (HUVEC) had a markedly reduced capacity to regenerate functional CD150+LSK cells (HSC) compared to other sources of arterial and venous EC. Transcriptional profiling revealed the overexpression of transforming growth factor- β1 (TGF-β1) in HUVEC and indicated that TGF-β1 driven transcriptional programs are highly active in these cells, a finding consistent with autocrine TGF-β1 signaling. Functional studies demonstrated that HSC regeneration by EC was potently inhibited by TGF-β1 and augmented by the ALK5 inhibitor SB431542, in a dose-dependent manner. Importantly, exposure of EC alone to TGF- β1 was sufficient to attenuate subsequent HSC self-renewal. Transcriptome analysis also identified hepatocyte growth factor (HGF) as a candidate EC-derived factor with the potential to enhance hematopoietic regeneration. HGF treatment of HUVEC activated endothelial Akt signaling and led to a >10-fold increase in HSC regeneration that could be blocked by the c-Met inhibitor PF04217903. HGF treatment also dramatically increased long-term multi-lineage hematopoiesis from HUVEC regenerated HSC. Our findings reveal a novel suppressive role for TGF-β1 in the vascular niche and demonstrate that EC-derived growth factors such as HGF have the potential to attenuate this suppression and significantly enhance HSC regeneration. Disclosures No relevant conflicts of interest to declare.

scholarly journals Increased Level of Vascular Endothelial Growth Factors by 4-hexylresorcinol is Mediated by Transforming Growth Factor-β1 and Accelerates Capillary Regeneration in the Burns in Diabetic Animals

2020 ◽  
Vol 21 (10) ◽  
pp. 3473 ◽  
Author(s):  
Dae-Won Kim ◽  
You-Young Jo ◽  
Umberto Garagiola ◽  
Je-Yong Choi ◽  
Yei-Jin Kang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Expression Level ◽  
Vascular Endothelial ◽  
Vascular Regeneration ◽  
Angiogenic Proteins ◽  
Tgf Β1

4-Hexyl resorcinol (4HR) is an organic compound and has been used in skin care application. 4HR is an M2-type macrophage activator and elevates vascular endothelial growth factor (VEGF) expression via the hypoxia-inducible factor (HIF)-independent pathway. As endothelial cells are important in wound healing, the human umbilical vein endothelial cells (HUVECs) were treated with 4HR, and changes in VEGF-A, -C, and transforming growth factor-β1 (TGF-β1) expression were investigated. The administration of 4HR increased the expression level of VEGF-A, -C, and TGF-β1. The application of TGF-β1 protein also increased the expression level of VEGF-A and -C. Knockdown with small interfering RNA (siRNA) targeting to TGF-β1 and the selective chemical inhibition (A83-01) to ALK5 confirmed the involvement of the TGF-β signaling pathway in the 4-HR-mediated VEGFs expression. 4HR application in a burn model of diabetic rats demonstrated an increased level of angiogenic proteins with wound healing. Compared to sericin application, the 4HR application group showed more prominent capillary regeneration. Collectively, 4HR activated TGF-β1/ALK5/VEGFs signaling in endothelial cells and induced vascular regeneration and remodeling for wound healing.

scholarly journals Platelet Transforming Growth Factor-β1 Induces Liver Sinusoidal Endothelial Cells to Secrete Interleukin-6

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1311
Author(s):  
Alexandre Balaphas ◽  
Jeremy Meyer ◽  
Remo Perozzo ◽  
Magali Zeisser-Labouebe ◽  
Sarah Berndt ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Liver Regeneration ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Liver Sinusoidal Endothelial Cells ◽  
Sinusoidal Endothelial Cells ◽  
Activated Platelets ◽  
Platelet Releasate ◽  
Tgf Β1

The roles and interactions of platelets and liver sinusoidal endothelial cells in liver regeneration are unclear, and the trigger that initiates hepatocyte proliferation is unknown. We aimed to identify the key factors released by activated platelets that induce liver sinusoidal endothelial cells to produce interleukin-6 (IL-6), a cytokine implicated in the early phase of liver regeneration. We characterized the releasate of activated platelets inducing the in vitro production of IL-6 by mouse liver sinusoidal endothelial cells and observed that the stimulating factor was a thermolabile protein. Following gel filtration, a single fraction of activated platelet releasate induced a maximal IL-6 secretion by liver sinusoidal endothelial cells (90.2 ± 13.9 versus control with buffer, 9.0 ± 0.8 pg/mL, p < 0.05). Mass spectroscopy analysis of this fraction, followed by in silico processing, resulted in a reduced list of 18 candidates. Several proteins from the list were tested, and only recombinant transforming growth factor β1 (TGF-β1) resulted in an increased IL-6 production up to 242.7 ± 30.5 pg/mL, which was comparable to non-fractionated platelet releasate effect. Using neutralizing anti-TGF-β1 antibody or a TGF-β1 receptor inhibitor, IL-6 production by liver sinusoidal endothelial cells was dramatically reduced. These results support a role of platelet TGF-β1 β1 in the priming phase of liver regeneration.

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