scholarly journals Thresholds of Endoglin Expression in Endothelial Cells Explains Vascular Etiology in Hereditary Hemorrhagic Telangiectasia Type 1

2021 ◽  
Vol 22 (16) ◽  
pp. 8948
Author(s):  
Georgios Galaris ◽  
Kévin Montagne ◽  
Jérémy H. Thalgott ◽  
Geoffroy J. P. E. Goujon ◽  
Sander van den Driesche ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Transforming Growth Factor ◽  
Clinical Manifestations ◽  
The Body ◽  
Vascular Lesions ◽  
Vascular Endothelial ◽  
Inherited Disease

Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in ENDOGLIN, which encodes an ancillary receptor for Transforming Growth Factor-β/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vasculature throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.

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

Cloning of the Promoter Region of Human Endoglin, the Target Gene for Hereditary Hemorrhagic Telangiectasia Type 1

Blood ◽  
1998 ◽  
Vol 92 (12) ◽  
pp. 4677-4690 ◽  
Author(s):  
Carlos Rı́us ◽  
Joshua D. Smith ◽  
Nuria Almendro ◽  
Carmen Langa ◽  
Luisa M. Botella ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Promoter Region ◽  
Transforming Growth Factor ◽  
Specific Activity ◽  
Specific Interaction ◽  
Regulatory Elements ◽  
Mobility Shift ◽  
Isolation And Characterization

Endoglin (CD105) is a cell surface component of the transforming growth factor-β (TGF-β) receptor complex highly expressed by endothelial cells. Mutations in the endoglin gene are responsible for the hereditary hemorrhagic telangiectasia type 1 (HHT1), also known as Osler-Weber-Rendu syndrome (OMIM 187300). This is an autosomal dominant vascular disorder probably caused by a haploinsufficiency mechanism displaying low levels of the normal protein. To understand the mechanisms underlying the regulated expression of endoglin, a genomic DNA clone containing 3.3 kb of the 5′-flanking sequence of the human endoglin gene has been isolated. The 5′-flanking region of the endoglin gene lacks consensus TATA and CAAT boxes, but contains two GC-rich regions and consensus motifs for Sp1, ets, GATA, AP-2, NFκB, and Mad, as well as TGF-β–, glucocorticoid-, vitamin D-, and estrogen-responsive elements. As determined by primer extension and 5′ RACE experiments, a cluster of transcriptional start sites was found to be located 350 bp upstream from the translation initiation codon. To analyze the endoglin promoter activity, the upstream −400/+341 fragment was fused to the luciferase gene and transient transfections were conducted in several cell types. This construct displayed a tissue-specific activity in human and bovine endothelial cells. Analysis of various deletion constructs showed the existence of a basal promoter region within the −81/+350 fragment as well as major transcriptional regulatory elements within the −400/−141 fragment. Electrophoretic mobility shift assays demonstrated the specific interaction of a member of the ets family with a consensus motif located at position −68. A promoter construct mutated at this ets sequence showed a much reduced activity as compared with the wild-type construct, supporting the involvement of this ets motif in the basal activity of the promoter. The endoglin promoter exhibited inducibility in the presence of TGF-β1, suggesting possible therapeutic treatments in HHT1 patients, in which the expression level of the normal endoglin allele might not reach the threshold required for its function. Isolation and characterization of the human endoglin promoter represents an initial step in elucidating the controlled expression of the endoglin gene.

Transforming growth factor-β stimulates the expression of endothelin mRNA by vascular endothelial cells

1989 ◽  
Vol 159 (3) ◽  
pp. 1435-1440 ◽  
Author(s):  
Hiroki Kurihara ◽  
Masao Yoshizumi ◽  
Takao Sugiyama ◽  
Fumimaro Takaku ◽  
Masashi Yanagisawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Vascular Endothelial Cells ◽  
Transforming Growth Factor Β ◽  
Vascular Endothelial

scholarly journals Platelets stimulate endothelial cells to synthesize type 1 plasminogen activator inhibitor. Evaluation of the role of transforming growth factor beta

Blood ◽  
1991 ◽  
Vol 77 (5) ◽  
pp. 1013-1019 ◽  
Author(s):  
SR Slivka ◽  
DJ Loskutoff
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Plasminogen Activator Inhibitor ◽  
Tgf Beta ◽  
Growth Factor Beta ◽  
Activator Inhibitor ◽  
Pai 1

Abstract A model system consisting of thrombin-stimulated bovine platelet releasates (PRthr) and bovine aortic endothelial cells (BAEs) was developed to determine if the interaction between platelets and endothelial cells regulates fibrinolysis. Zymographic analysis indicated that PRthr treatment of BAEs decreases urokinase and increases type 1 plasminogen activator inhibitor (PAI-1) activity. Although PRthr did not affect the overall rate of BAE protein synthesis, it increased PAI-1 biosynthesis within 6 hours. This increase was complete by 12 hours, with maximum stimulation at 10 to 15 micrograms/mL PRthr (1 microgram approximately 10(7) platelets). Neutralizing antibodies to transforming growth factor beta (TGF beta) reduced this effect by 75%. Treatments that activate latent TGF beta (eg, acidification or plasmin) increased this effect approximately fivefold, suggesting that TGF beta in PRthr exists in both a latent (approximately 80%) and an active (approximately 20%) form. In contrast to PRthr, adenosine diphosphate-prepared platelet releasates did not increase PAI-1 synthesis before acidification, indicating that they contain only the latent form of TGF beta. These results suggest that platelets can modulate the fibrinolytic system of the endothelium through the release of TGF beta, and that the mechanism by which the platelets are activated can influence the relative amount of active TGF beta.

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