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Abstract Number: 1506

Primary Human Scleroderma Dermal Endothelial Cells Exhibit Defective Angiogenesis

Pei-Suen Tsou1, Bradley J. Rabquer2, Beatrix Balogh2, Ann Kendzicky2, Bashar Kahaleh3, Elena Schiopu4, Dinesh Khanna5 and Alisa E. Koch6, 1Internal Medicine, Division of Rheumatology, University of Michigan Medical Center, Ann Arbor, MI, 2University of Michigan Medical School, Ann Arbor, MI, 3Medicine/Rheumatology, University of Toledo, Toledo, OH, 4Rheumatology/Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 5Division of Rheumatology, University of Michigan Medical Center, Ann Arbor, MI, 6Internal Medicine - Rheumatology, University of Michigan Medical School, Ann Arbor, MI

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Angiogenesis, chemokines, endothelial cells and scleroderma

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Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Angiogenesis, the formation of new blood vessels, plays a critical role in a number of pathological processes including systemic sclerosis (scleroderma, SSc). SSc is a multifactoral disorder that is characterized by early inflammation, excessive extracellular matrix deposition, and vascular abnormalities. In this study we determined if the endothelial cells (ECs) isolated from SSc skin mount a proangiogenic response towards angiogenic chemokines, including growth-regulated protein-γ (Gro-γ/CXCL3), granulocyte chemotactic protein-2 (GCP-2/CXCL6), and CXCL16. The expression of transcription factors inhibitor of DNA-binding protein 1 and 3 (Id-1 and 3), which are required for ECs to mount an angiogenic response, were also examined.

Methods:

Skin biopsies from the distal forearm (more involved) were obtained from patients with SSc. Normal (NL) skin tissue was obtained from the tissue procurement service of the University of Michigan. ECs were isolated from skin biopsies via magnetic selection. Immunofluorescence staining of EC markers such as CD31 and von Willebrand factor (vWF), as well as fibroblast markers such as collagen I and α-smooth muscle actin (αSMA) was performed. To determine if chemokines mediate specific angiogenic events in SSc ECs, chemotaxis assays were performed. ECs were stimulated with chemokines to determine which signaling pathways were activated. The expression of Id-1 and 3 were quantified by quantitative PCR.

Results:

Both NL and SSc ECs stained positive for EC markers while they did not stain for fibroblast markers. SSc ECs migrated toward phorbol- 12- myristate- 13- acetate (PMA) but not to basic fibroblast growth factor (bFGF) compared to their corresponding controls, dimethyl sulfoxide (DMSO) or phosphate buffered saline (PBS). GCP-2/CXCL6 dose dependently induced both NL and SSc EC migration. In contrast, the ability of Gro-γ/CXCL3 and CXCL16 to promote cell migration was hampered in SSc ECs compared to NL ECs. GCP-2/CXCL6 stimulated the phosphorylation of Akt, cJun, Erk1/2, NFkB p65, and p38 kinases in a dose dependent manner in NL ECs, while only cJun, Erk1/2, and p38 kinases in SSc ECs. CXCL16 stimulated Akt, Erk1/2, NFkB p65, and p38 kinases phosphorylation in NL ECs, while only cJun, Erk1/2, and p38 kinases in SSc ECs. The mRNA levels of Id-1 and Id-3 in SSc ECs were 2.5 and 2.1 fold lower compared to NLs (n=3).

Conclusion:

Our results show that Gro-γ/CXCL3 and CXCL16 induce anigogenic activity in NL but not SSc ECs. This might be due to the differences in the signaling pathways activated by these chemokines in NL vs. SSc ECs. In addition, the lower expression of transcription factors Id-1 and Id-3 might also decrease the angiogenic response in these cells. The inability of proangiogenic chemokines to promote EC migration provides an additional mechanism for the impaired angiogenesis that characterizes SSc.


Disclosure:

P. S. Tsou,
None;

B. J. Rabquer,
None;

B. Balogh,
None;

A. Kendzicky,
None;

B. Kahaleh,
None;

E. Schiopu,

United Therapeutics,

8;

D. Khanna,

Actelion, Gilead, Genentech, ISDIN, and United Therapeutics,

2,

Actelion, Gilead, Genentech, ISDIN, and United Therapeutics,

5,

Actelion, Gilead, Genentech, ISDIN, and United Therapeutics,

8;

A. E. Koch,
None.

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