Angiotensin II mediates the high-glucose-induced endothelial-to-mesenchymal transition in human aortic endothelial cells

Tang, Ri‐Ning; Li, Qing; Lv, Lin‐Li; Dai, Houyong; Zheng, Min; Ma, Kun-Ling; Liu, Bi‐Cheng

doi:10.1186/1475-2840-9-31

Cited by 46 publications

(34 citation statements)

References 29 publications

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“…Recent studies have indicated that EndoMT can contribute to the progression of fibrotic diseases, and Ang II has been implicated in this process [24-27]. To determine whether EndoMT could serve as a source of activated fibroblasts, we performed double-fluorescence staining for VE-cadherin and FSP1 in the skin samples from Ang II- and PBS-treated mice (Figure 7A).…”

Section: Resultsmentioning

confidence: 99%

Angiotensin II induces skin fibrosis: a novel mouse model of dermal fibrosis

et al. 2012

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IntroductionSystemic sclerosis (SSc) is an autoimmune inflammatory disorder of unknown etiology characterized by fibrosis of the skin and internal organs. Ang II (angiotensin II), a vasoconstrictive peptide, is a well-known inducer of kidney, heart, and liver fibrosis. The goal of this study was to investigate the profibrotic potential of Ang II in the mouse skin.MethodsAng II was administered by subcutaneous osmotic mini pumps to C57BL/6 male mice. Collagen-content measurements were performed with Gomori Trichrome staining and hydroxyproline assay. The mRNA expression level of collagens, TGF-β1, TGF-β2, TGF-β3, CTGF, αSMA, CD3, Emr1, CD45/B220, MCP1, and FSP1 were quantified with real-time polymerase chain reaction (PCR). Immunostaining was performed for markers of inflammation and fibrosis, including, phospho-Smad2, αSMA, CD3, Mac3, CD45/B220, and CD163B. Fibrocytes were identified by double staining with CD45/FSP1 and CD45/PH4. Endothelial cells undergoing endothelial-to-mesenchymal transition (EndoMT) were identified by double staining with VE-cadherin/FSP1.ResultsAng II-infused mice develop prominent dermal fibrosis in the area proximal to the pump, as shown by increased collagen and CTGF mRNA levels, increased hydroxyproline content, and more tightly packed collagen fibers. In addition, elevated mRNA levels of TGF-β2 and TGF-β3 along with increased expression of pSmad2 were observed in the skin of Ang II-treated mice. Dermal fibrosis was accompanied by an increased number of infiltrating fibrocytes, and an increased number of αSMA-positive cells, as well as CD163B+ macrophages in the upper dermis. This correlated with significantly increased mRNA levels of αSMA, Emr1, and MCP1. Infiltration of CD3-, CD45/B220-, and Mac3-positive cells was observed mainly in the hypodermis. Furthermore, an increased number of double-positive VE-cadherin/FSP1 cells were detected in the hypodermis only.ConclusionsThis work demonstrates that Ang II induces both inflammation and fibrosis in the skin via MCP1 upregulation and accumulation of activated fibroblasts. Additionally, our data suggest that populations of these fibroblasts originate from circulating blood cells. Ang II infusion via osmotic minipumps could serve as a useful mouse model of skin fibrosis to gain new insights into pathogenic mechanisms and to test new antifibrotic therapies.

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Section: Resultsmentioning

confidence: 99%

Angiotensin II induces skin fibrosis: a novel mouse model of dermal fibrosis

et al. 2012

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“…During the past decade, the notion that SMCs undergo differentiation into chondrogenic cells to participate in MAC has already gained acceptance [5,7]. However, conventional distinctions among vascular cell lineages are becoming less clear as our studies and other investigators determine that ECs could also trans-differentiate into SMCs, a process known as EndMT [10,11,18,19]. Furthermore, studies found that EndMT has the ability to convert cells into MSCs and then differentiate into chondrocytes [12].…”

Section: Discussionmentioning

confidence: 99%

High glucose mediates endothelial-to-chondrocyte transition in human aortic endothelial cells

Tang

Gao

et al. 2012

Cardiovasc Diabetol

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BackgroundVascular calcification is one of the common complications in diabetes mellitus. Many studies have shown that high glucose (HG) caused cardiovascular calcification, but its underlying mechanism is not fully understood. Recently, medial calcification has been most commonly described in the vessels of patients with diabetes. Chondrocytes were involved in the medial calcification. Recent studies have shown that the conversion into mesenchymal stem cells (MSCs) via the endothelial-to-mesenchymal transition (EndMT) could be triggered in chondrocytes. Our previous research has indicated that HG induced EndMT in human aortic endothelial cells (HAECs). Therefore, we addressed the question of whether HG-induced EndMT could be transitioned into MSCs and differentiated into chondrocytes.MethodsHAECs were divided into three groups: a normal glucose (NG) group, HG group (30 mmol/L), and mannitol (5.5 mmol/L NG + 24.5 mmol/L) group. Pathological changes were investigated using fluorescence microscopy and electron microscopy. Immunofluorescence staining was performed to detect the co-expression of endothelial markers, such as CD31, and fibroblast markers, such as fibroblast-specific protein 1 (FSP-1). The expression of FSP-1 was detected by real time-PCR and western blots. Endothelial-derived MSCs were grown in MSC medium for one week. The expression of the MSCs markers STRO-1, CD44, CD10 and the chondrocyte marker SOX9 was detected by immunofluorescence staining and western blots. Chondrocyte expression was detected by alcian blue staining. Calcium deposits were analyzed by alizarin red staining.ResultsThe incubation of HAECs exposed to HG resulted in a fibroblast-like phenotype. Double staining of the HAECs indicated a co-localization of CD31 and FSP-1. The expression of FSP-1 was significantly increased in the HG group, and the cells undergoing EndMT also expressed STRO-1, CD44 and SOX9 compared with the controls (P < 0.05). Additionally, alcian blue staining in the HG group was positive compared to the NG group. Consistent with the evaluation of SOX9 expression, calcium deposits analyzed by alizarin red staining were also enhanced by the HG treatment. Specifically, we showed that HG-induced EndMT is accompanied by the activation of the canonical Snail pathway.ConclusionsOur study demonstrated that HG could induce endothelial cells transdifferentiation into chondrocyte-like cells via the EndMT, which is mediated in part by the activation of the Snail signaling pathway.

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“…Angiotensin II was measured in the supernatant using a radioimmunoassay as previously described [19]. A commercial radioimmunoassay kit (Beifang, China) was used to measure angiotensin II.…”

Section: Angiotensin II Measurementsmentioning

confidence: 99%