Scleroderma dermal microvascular endothelial cells exhibit defective response to pro-angiogenic chemokines

Tsou, Pei Suen; Rabquer, Bradley J.; Ohara, Ray A.; Stinson, William A.; Campbell, Phillip L.; Amin, M. Asif; Balogh, Beatrix; Zakhem, George A.; Renauer, Paul; Lozier, Ann; Arasu, Eshwar; Haines, G. Kenneth; Kahaleh, Bashar; Schiopu, Elena; Khanna, Dinesh; Koch, Alisa E.

doi:10.1093/rheumatology/kev399

Cited by 26 publications

(27 citation statements)

References 36 publications

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“…eNOS = endothelial cell nitric oxide synthase (see Figure 1 for other definitions). adox), we showed previously that these cells do respond to higher levels of VEGF (33), which strengthens the argument that overexpressing CYR-61 in fibroblasts might increase the angiogenic potential of SSc ECs.…”

Section: Discussionsupporting

confidence: 85%

“…This is possible, since cross‐talk between ECs and fibroblasts in SSc has been documented . Although VEGF has a limited effect on SSc ECs (the so‐called VEGF paradox), we showed previously that these cells do respond to higher levels of VEGF , which strengthens the argument that overexpressing CYR‐61 in fibroblasts might increase the angiogenic potential of SSc ECs.…”

Section: Discussionsupporting

confidence: 78%

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Identification of Cysteine‐Rich Angiogenic Inducer 61 as a Potential Antifibrotic and Proangiogenic Mediator in Scleroderma

Tsou

Khanna

Sawalha

2019

Arthritis & Rheumatology

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Objective We previously identified CYR61 as a histone deacetylase 5 (HDAC‐5)–repressed gene in systemic sclerosis (SSc; scleroderma) endothelial cells (ECs). When overexpressed, cysteine‐rich angiogenic inducer 61 (CYR‐61) promoted angiogenesis in SSc ECs. This study was undertaken to examine the role of CYR‐61 in fibrosis and determine the mechanisms involved in CYR‐61–mediated angiogenesis in SSc. Methods Dermal ECs and fibroblasts were isolated from biopsy specimens from healthy subjects and patients with SSc. CYR‐61 level was determined by quantitative polymerase chain reaction, Western blotting, and enzyme‐linked immunosorbent assay. CYR‐61 was overexpressed using a CYR61 vector or knocked down using small interfering RNA, and functional and mechanistic studies were then conducted in fibroblasts and ECs. Results Lower CYR61 messenger RNA levels were observed in dermal fibroblasts and ECs from SSc patients than in those from healthy controls. In SSc fibroblasts, overexpression of CYR‐61 led to significant reduction in the expression of profibrotic genes, including COL1A1 (P = 0.002) and ACTA2 (P = 0.04), and an increase in the expression of matrix‐degrading genes, including MMP1 (P = 0.002) and MMP3 (P =0.004), and proangiogenic VEGF (P = 0.03). The antifibrotic effect of CYR‐61 was further demonstrated by delay in wound healing, inhibition of gel contraction, inactivation of the transforming growth factor β pathway, and early superoxide production associated with senescence in SSc fibroblasts. In SSc ECs, overexpression of CYR‐61 led to increased production of vascular endothelial cell growth factor. The proangiogenic effects of CYR‐61 were mediated by signaling through αvβ3 receptors and downstream activation of AMP‐activated protein kinase, AKT, and the endothelial cell nitric oxide synthase/nitric oxide pathway system. Conclusion CYR‐61, which is epigenetically regulated by HDAC‐5, is a potent antifibrotic and proangiogenic mediator in SSc. Therapeutic intervention to promote CYR‐61 activity or increase CYR‐61 levels might be of benefit in SSc.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 78%

Identification of Cysteine‐Rich Angiogenic Inducer 61 as a Potential Antifibrotic and Proangiogenic Mediator in Scleroderma

Tsou

Khanna

Sawalha

2019

Arthritis & Rheumatology

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“…Indeed, endothelial dysfunction is considered a pivotal factor contributing to peripheral vessel remodelling in SSc 3 15 41. A defective response to proangiogenic stimuli and several functional defects, such as an impaired ability to organise into capillary-like tubes in vitro, have been extensively reported in SSc-dMVECs 28 29 35 41 46. Moreover, transcriptome profiling studies have revealed profound differences in the expression of genes encoding a variety of angiogenic regulators between SSc-dMVECs and H-dMVECs 41 47.…”

Section: Discussionmentioning

confidence: 99%

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

et al. 2017

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“…Previous studies on this aspect have proven that through promoting the expression of genes such MMP‐2 and MMP‐9, Id‐1 can promote damage to structures of the basement membrane and accelerate the infiltration of tumors in colorectal cancer tissues . Furthermore, Id‐1 can induce the proliferation of endothelial cells in blood vessels and promote the formation of blood capillaries and lymphatic microvessels through increasing expression of vascular endothelial growth factor (VEGF), providing the necessary material foundation for the infiltration and metastasis of tumors . The results of the Transwell chamber and Matrigel experiments revealed that the migration and invasion abilities of SW480 and HT‐29 human colonic cancer cells with the interfering sequence of Id‐1 were significantly lower than that in the blank groups and blank load groups, proving that the overexpression of Id‐1 could promote the invasion and metastasis of tumors.…”

Section: Discussionmentioning

confidence: 99%

A study of the impact of inhibitors of DNA binding‐1 on proliferation and migration in human colon carcinoma cells

Wang

Xue

et al. 2019

The Kaohsiung J of Med Scie

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This study aims to explore the effect of an inhibitor of DNA binding‐1 (Id‐1) on the proliferation and migration of human colon carcinoma cell line SW480 and HT‐29. SW480 and HT‐29 cells transfected with Id‐1‐interference sequence were assigned to the experimental groups (inhibition groups 1 and 2), and SW480 and HT‐29 cells with blank interference sequence (blank groups) and blank load transfection (blank load groups) were assigned as the control groups. The expression of Id‐1 in six groups was detected by reverse transcription‐polymerase chain reaction (RT‐PCR) and Western blot. Cell proliferation in vitro was assessed by MTT assay. RT‐PCR and Western blot results demonstrated that the mRNA and protein expressions of Id‐1 in the inhibition group 1 were lower than those in the blank group 1 and blank load group 1. RT‐PCR and Western blot results revealed that the mRNA and protein expressions of Id‐1 were lower in the inhibition group 2 than in the blank group 2 and blank load group 2. The results of the growth curve revealed that proliferation ability was significantly weaker from the third day in the inhibition groups 1 and 2 than in the blank group and blank load group. Transwell chamber experiment and Matrigel invasion assay revealed that the number of Transwell cells significantly decreased in the inhibition groups 1 and 2 than in the blank groups and blank load groups (P < 0.01). Id‐1 significantly promotes the proliferation and migration of human colon carcinoma cell lines SW480 and HT‐29.

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Scleroderma dermal microvascular endothelial cells exhibit defective response to pro-angiogenic chemokines

Cited by 26 publications

References 36 publications

Identification of Cysteine‐Rich Angiogenic Inducer 61 as a Potential Antifibrotic and Proangiogenic Mediator in Scleroderma

Identification of Cysteine‐Rich Angiogenic Inducer 61 as a Potential Antifibrotic and Proangiogenic Mediator in Scleroderma

Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis

A study of the impact of inhibitors of DNA binding‐1 on proliferation and migration in human colon carcinoma cells

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