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Effects of Fibrinogen on Endothelin‐1 Production and F‐actin Formation: Possible Mechanisms of Vasoconstriction
Author(s) -
Lominadze David,
Tyagi Neetu,
Moshal Karni S.,
Tyagi Suresh C.,
Dean William L.,
Roberts Andrew M.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a284-c
Subject(s) - vasoconstriction , chemistry , endothelin 1 , mapk/erk pathway , extracellular , endothelin receptor , receptor , vascular smooth muscle , microbiology and biotechnology , kinase , medicine , endocrinology , biochemistry , biology , smooth muscle
We showed that fibrinogen (Fg) constricted arterioles in rat cremaster muscle through binding to endothelial cell (EC) intercellular adhesion molecule‐1 (ICAM‐1) ( AJP , 2005; 288 (3):–64). This vasoconstriction was normalized by blocking endothelin type A receptors, suggesting a link between Fg binding to ECs and production of endothelin‐1 (ET‐1). To determine if Fg binding causes release of ET‐1 from ECs, rat coronary microvascular ECs (CMEC) were cultured to confluency in six‐well plates, and incubated with culture medium, with various concentrations (0.01 ‐ 4 mg/ml) of Fg, or with Fg (4 mg/ml) in the presence of extracellular signal regulated kinase (ERK) activity inhibitor PD98059 (50 μM) for 30 min at 37 o C. After incubation, the supernatant from each well was collected and content of ET‐1 was measured by an ET‐1 ELISA kit. Fg caused dose‐dependent release of ET‐1 from ECs. In separate studies, phosphorylations of serine, threonine, and ERK‐1/2, determined by Western blot analysis, was increased in the CMECs treated with 4 mg/ml Fg. Fg caused formation of filamentous actin (F‐actin) in ECs and resulted in formation of gaps between cells. Formation of F‐actin and the gaps between ECs were diminished by blocking ICAM‐1, and to a lesser extent α 5 β 1 integrin, or by inhibiting the activity of ERK with PD98059 (50 μM). These results indicate a new functional role of Fg that could exacerbate an increase in peripheral vascular resistance during diseases such as hypertension, diabetes, and stroke, that are characterized by an increased plasma Fg content. Supported by AHA‐National to DL