Session Title: Vasculitis: Pathogenesis
Session Type: Abstract Submissions (ACR)
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
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 (TaqmanR Gene Expression Assay) from Applied Biosystems. COL1 and COL3 protein production was determined by ELISA (Takara and USNC Biological) kits respectively.
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
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
M. A. Alba,
M. C. Cid,
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