Endothelin-1 (ET-1) Induces Extracellular Matrix Protein Production by Human Temporal Artery Derived Myointimal Cells. A Mechanism Potentially Leading to Intimal Hyperplasia and Vascular Occlusion in Giant-Cell Arteritis

Ester Planas-Rigol¹, Marc Corbera-Bellalta², Marco A. Alba³, Itziar Tabera-Bahillo³, Sergio Prieto-Gonzalez³, Georgina espigol-Frigole³, Jose Hernandez-Rodriguez⁴, Ester Lozano⁵ and Maria C. Cid⁶, ¹Systemic Autoimmune Diseases, Vasculitis Research Unit. Hospital Clínic. University of Barcelona. IDIBAPS, Barcelona, Spain, ²Hospital Clinic University Barcelona, Hospital Clinic University Barcelona, Barcelona, Spain, ³Vasculitis research Unit, systemic autoimmune diseases department. Idibaps., Hospital Clinic University Barcelona, Barcelona, Spain, ⁴Vasculitis research Unit, systemic autoimmune diseases department. Idibaps., Hospital Clínic. University of Barcelona. IDIBAPS, Barcelona, Spain, ⁵Vasculitis research Unit, systemic autoimmune diseases department. Idibaps., Hospital Clinic University Barcelona, ⁶Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: extracellular matrix proteins, giant cell arteritis, inflammation and vasculitis

Session Information

Session Title: Vasculitis: Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Endothelin-1 (ET-1) is the main isoform of the Endothelin family. It is also the most powerful vasoconstrictor identified. ET-1 is constitutively produced in blood vessels by endothelial cells and vascular smooth muscle cells (VSMC). VSMC express two endothelin receptors: Endothelin receptor A and B (ETAR and ETBR) but the main effect of vasoconstriction may be the result of the interaction between ET-1 and ETAR. Transforming Growth Factor β1 is a fibrogenic cytokine and recent studies suggest that ET-1 contributes to the fibrogenic effect of TGFβ by fibroblasts.

To investigate whether ET-1 and TGFβ may contribute to vascular occlusion by inducing pro-fibrotic responses in cultured vascular myointimal cells

Methods:

VSMC were obtained from cultured human temporal artery sections obtained for diagnostic purposes as described (Ann Rheum Dis. 2008 Nov; 67(11):1581-8). ET-1, TGFb, collagen type I (COL1) and type III (COL3) expression was assessed by quantitative real-time PCR (Taqman^R Gene Expression Assay) from Applied Biosystems. COL1 and COL3 protein production was determined by ELISA (Takara and USNC Biological) kits respectively.

Results:

ET-1 and TGFb up regulated COL1, COL3 expression by VSMC at the mRNA and protein level. This increase was inhibited by ETAR receptor antagonist BQ123 and partially abrogated by ALK5 inhibitor SB525334.

ET-1 induced indeed a remarkable early expression of TGFβ and TGFb induced, in turn, a later induction of ET-1. A double blockade of these cytokines enhanced the inhibition of COL1 and COL3 expression suggesting that collagen production by VSMC may be dependent of both ET-1 and TGFβ.

Phenotypic changes in ET-1-treated-VSMC were also observed. These cells became adherent earlier than untreated ones. Treatment with BQ123 reverted this phenotype suggesting that ET-1 may have an important role in the regulation of VSMC adhesion and migration

Conclusion:

ET-1 may contribute to intimal hyperplasia directly by inducing collagen type I and III by human medium-size artery derived myointimal cells. Since ET-1 and TGFb are expressed in GCA lesions these preliminary results suggest that ETAR and ALK5 receptor antagonists may prevent intimal hyperplasia and vascular occlusion in GCA.

Supported by SAF 08/04328 and SAF 11/30073

Disclosure:

E. Planas-Rigol,
None;

M. Corbera-Bellalta,
None;

M. A. Alba,
None;

I. Tabera-Bahillo,
None;

S. Prieto-Gonzalez,
None;

G. espigol-Frigole,
None;

J. Hernandez-Rodriguez,
None;

E. Lozano,
None;

M. C. Cid,
None.

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