Abstract 222: Dkk1 and Msx2-Wnt7b Signaling Reciprocally Regulate the Endothelial-Mesenchymal Transition in Aortic Endothelial Cells

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Su-Li Cheng ◽  
Jian-su Shao ◽  
Abraham Behrmann ◽  
Karen Krchma ◽  
Dwight A Towler
Keyword(s):  
Endothelial Cells ◽  
Mesenchymal Cell ◽  
Type I ◽  
Cuboidal Cell ◽  
Aortic Endothelial Cells ◽  
Mesenchymal Transition ◽  
Cell Responses ◽  
The Impact ◽  
Endothelial Mesenchymal Transition ◽  
Aortic Endothelial

Objective Endothelial cells (ECs) can undergo an endothelial-mesenchymal transition (EndMT) during tissue fibrosis. Wnt- and Msx2-regulated signals participate in arteriosclerotic calcification and fibrosis. We studied the impact of Wnt7, Msx2, and Dkk1 (Wnt7 antagonist) on EndMT in primary aortic endothelial cells (AoECs). Methods and Results Transduction of AoECs with vectors expressing Dkk1 suppressed EC differentiation and induced a mineralizing myofibroblast phenotype. Dkk1 suppressed claudin 5, PECAM, cadherin 5 (Cdh5), Tie1 and Tie2. Dkk1 converted the cuboidal cell monolayer into a spindle-shaped multilayer and inhibited EC cord formation. Myofibrogenic and osteogenic markers - e.g., SM22, type I collagen, Osx, Runx2, alkaline phosphatase – were upregulated by Dkk1 via activin-like kinase / Smad pathways. Dkk1 increased fibrosis and mineralization of AoECs cultured under osteogenic conditions - the opposite of mesenchymal cell responses. Msx2 and Wnt7b maintained the “cobblestone” morphology of differentiated ECs and promoted EC marker expression. Deleting EC Wnt7b with the Cdh5-Cre transgene in Wnt7b(fl/fl);LDLR-/- mice upregulated aortic osteogenic genes (Osx, Sox9, Runx2, Msx2) and nuclear pSmad1/5, and increased collagen accumulation. Conclusions Dkk1 enhances EndMT in AoECs, while Msx2-Wnt7 signals stabilize EC phenotype. EC responses to Dkk1, Wnt7b, and Msx2 are the opposite of mesenchymal cell responses, coupling EC phenotypic stability with osteofibrogenic predilection during arteriosclerosis.

scholarly journals Endothelial-Mesenchymal Transition in Heart Failure With a Preserved Ejection Fraction: Insights Into the Cardiorenal Syndrome

2021 ◽  
Author(s):  
María Valero-Muñoz ◽  
Albin Oh ◽  
Elizabeth Faudoa ◽  
Rosa Bretón-Romero ◽  
Fatima El Adili ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Ejection Fraction ◽  
Cardiorenal Syndrome ◽  
Preserved Ejection Fraction ◽  
Aortic Endothelial Cells ◽  
Mesenchymal Transition ◽  
Human Aortic Endothelial Cells ◽  
Endothelial Mesenchymal Transition ◽  
Aortic Endothelial

Background: The management of clinical heart failure with a preserved ejection fraction (HFpEF) is often complicated by concurrent renal dysfunction, known as the cardiorenal syndrome. This, combined with the notable lack of evidence-based therapies for HFpEF, highlights the importance of examining mechanisms and targetable pathways in HFpEF with the cardiorenal syndrome. Methods: HFpEF was induced in mice by uninephrectomy, infusion of d -aldosterone (HFpEF; N=10) or saline (Sham; N=8), and given 1% NaCl drinking water for 4 weeks. Renal fibrosis and endothelial-mesenchymal transition (endo-MT) were evident once HFpEF developed. Human aortic endothelial cells were treated for 4 days with 10% serum obtained from patients with chronically stable HFpEF with the cardiorenal syndrome (N=12) and compared with serum-treated human aortic endothelial cells from control subjects (no cardiac/renal disease; N=12) to recapitulate the in vivo findings. Results: Kidneys from HFpEF mice demonstrated hypertrophy, interstitial fibrosis (1.9-fold increase; P <0.05) with increased expression of endo-MT transcripts, including pdgfrβ (platelet-derived growth factor receptor β), snail, fibronectin, fsp1 (fibroblast-specific protein 1), and vimentin by 1.7- ( P =0.004), 1.7- ( P =0.05), 1.8- ( P =0.005), 2.6- ( P =0.001), and 2.0-fold ( P =0.001) versus Sham. Immunostaining demonstrated co-localization of CD31 and ACTA2 (actin α2) in kidney sections suggesting evidence of endo-MT. Similar to the findings in HFpEF mice, comparable endo-MT markers were also significantly elevated in human aortic endothelial cells treated with serum from patients with HFpEF compared with human aortic endothelial cells treated with serum from control subjects. Conclusions: These translational findings demonstrate a plausible role for endo-MT in HFpEF with cardiorenal syndrome and may have therapeutic implications in drug development for patients with HFpEF and concomitant renal dysfunction.

scholarly journals Endothelial to Mesenchymal Transition: Role in Physiology and in the Pathogenesis of Human Diseases

2019 ◽  
Vol 99 (2) ◽  
pp. 1281-1324 ◽  
Author(s):  
Sonsoles Piera-Velazquez ◽  
Sergio A. Jimenez
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Transforming Growth Factor ◽  
Mesenchymal Cell ◽  
Human Diseases ◽  
Type I ◽  
Mesenchymal Transition ◽  
Regulatory Pathways ◽  
Complex Biological Process ◽  
Endothelial To Mesenchymal Transition

Numerous studies have demonstrated that endothelial cells are capable of undergoing endothelial to mesenchymal transition (EndMT), a newly recognized type of cellular transdifferentiation. EndMT is a complex biological process in which endothelial cells adopt a mesenchymal phenotype displaying typical mesenchymal cell morphology and functions, including the acquisition of cellular motility and contractile properties. Endothelial cells undergoing EndMT lose the expression of endothelial cell-specific proteins such as CD31/platelet-endothelial cell adhesion molecule, von Willebrand factor, and vascular-endothelial cadherin and initiate the expression of mesenchymal cell-specific genes and the production of their encoded proteins including α-smooth muscle actin, extra domain A fibronectin, N-cadherin, vimentin, fibroblast specific protein-1, also known as S100A4 protein, and fibrillar type I and type III collagens. Transforming growth factor-β1 is considered the main EndMT inducer. However, EndMT involves numerous molecular and signaling pathways that are triggered and modulated by multiple and often redundant mechanisms depending on the specific cellular context and on the physiological or pathological status of the cells. EndMT participates in highly important embryonic development processes, as well as in the pathogenesis of numerous genetically determined and acquired human diseases including malignant, vascular, inflammatory, and fibrotic disorders. Despite intensive investigation, many aspects of EndMT remain to be elucidated. The identification of molecules and regulatory pathways involved in EndMT and the discovery of specific EndMT inhibitors should provide novel therapeutic approaches for various human disorders mediated by EndMT.

Human aortic endothelial cells express the type I but not the type II receptor for interleukin-1 (IL-1)

1992 ◽  
Vol 153 (3) ◽  
pp. 583-588 ◽  
Author(s):  
Ann L. Akeson ◽  
Laura B. Mosher ◽  
Connie W. Woods ◽  
Kendra K. Schroeder ◽  
Terry L. Bowlin
Keyword(s):  
Endothelial Cells ◽  
Interleukin 1 ◽  
Type I ◽  
Type Ii ◽  
Aortic Endothelial Cells ◽  
Human Aortic Endothelial Cells ◽  
Aortic Endothelial

Glucose enhances expression of TRPC1 and calcium entry in endothelial cells

2010 ◽  
Vol 298 (1) ◽  
pp. H171-H178 ◽  
Author(s):  
N. B. Bishara ◽  
H. Ding
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Current Data ◽  
Aortic Endothelial Cells ◽  
Bovine Aortic Endothelial Cells ◽  
Transient Receptor ◽  
The Impact ◽  
Aortic Endothelial

Hyperglycemia is a major risk factor for endothelial dysfunction and vascular disease, and in the current study, the link to glucose-induced abnormal intracellular Ca2+ (Cai2+) homeostasis was explored in bovine aortic endothelial cells in high glucose (HG; 25 mmol/l) versus low glucose (LG; 5.5 mmol/l; control). Transient receptor potential 1 (TRPC1) ion channel protein, but not TRPC3, TRPC4, or TRPC6 expression, was significantly increased in HG versus LG at 72 h. HG for 4, 24, and 72 h did not change basal Cai2+ or ATP-induced Cai2+ release; however, the amplitude of sustained Cai2+ was significantly increased at 24 and 72 h and reduced by low concentration of the putative, but nonspecific, TRPC blockers, gadolinium, SKF-96365, and 2-aminoethoxydiphenyl borate. Treatment with TRPC1 antisense significantly reduced TRPC1 protein expression and ATP-induced Ca2+ entry in bovine aortic endothelial cells. Although the link between HG-induced changes in TRPC1 expression, enhanced Ca2+ entry, and endothelial dysfunction require further study, the current data are suggestive that targeting these pathways may reduce the impact of HG on endothelial function.

scholarly journals MDP Up-Regulates the Gene Expression of Type I Interferons in Human Aortic Endothelial Cells

Molecules ◽  
2012 ◽  
Vol 17 (4) ◽  
pp. 3599-3608 ◽  
Author(s):  
Qingshan Lv ◽  
Mei Yang ◽  
Xueting Liu ◽  
Lina Zhou ◽  
Zhilin Xiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Type I Interferons ◽  
Type I ◽  
Aortic Endothelial Cells ◽  
Human Aortic Endothelial Cells ◽  
Aortic Endothelial

scholarly journals Protective Effects of Collagen Tripeptides in Human Aortic Endothelial Cells by Restoring ROS-Induced Transcriptional Repression

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2226
Author(s):  
Hidehito Saito-Takatsuji ◽  
Yasuo Yoshitomi ◽  
Yasuhito Ishigaki ◽  
Shoko Yamamoto ◽  
Noriaki Numata ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcriptional Repression ◽  
Type I Collagen ◽  
Biological Effects ◽  
Osteoblastic Cell ◽  
Type I ◽  
Osteoblastic Cell Line ◽  
Aortic Endothelial Cells ◽  
Human Aortic Endothelial Cells ◽  
Aortic Endothelial

Collagen tripeptide (CTP) is defined as a functional food material derived from collagenase digests of type I collagen and contains a high concentration of tripeptides with a Gly-X-Y sequence. CTP has several biological effects, including the acceleration of fracture healing, ameliorating osteoarthritis, and improving dryness and photoaging of the skin. Recently, an antiatherosclerotic effect of CTP has been reported, although its molecular mechanism is yet to be determined. In this study, we examined the effects of CTP on primary cultured human aortic endothelial cells (HAECs) under oxidative stress, because oxidative endothelial dysfunction is a trigger of atherosclerosis. DNA microarray and RT-qPCR analyses showed that CTP treatment recovered the downregulated expression of several genes, including the interleukin-3 receptor subunit alpha (IL3RA), which were suppressed by reactive oxygen species (ROS) treatment in HAECs. Furthermore, IL3RA knockdown significantly decreased the viability of HAECs compared with control cells. RT-qPCR analysis also showed that solute carrier 15 family peptide transporters, which are involved in CTP absorption into cells, were expressed in HAECs at levels more than comparable to those of a CTP-responsive human osteoblastic cell line. These results indicated that CTP exerts a protective effect for HAECs, at least in part, by regulating the recovery of ROS-induced transcriptional repression.

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