Premium
Endothelin receptor selectivity: evidence from in vitro and pre‐clinical models of scleroderma
Author(s) -
Shiwen X.,
Leask A.,
Abraham D. J.,
Fonseca C.
Publication year - 2009
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.2009.02117.x
Subject(s) - fibrosis , receptor , extracellular matrix , vascular smooth muscle , biology , signal transduction , vascular remodelling in the embryo , elastin , immunology , cancer research , pathology , medicine , microbiology and biotechnology , endocrinology , smooth muscle
Scleroderma [systemic sclerosis (SSc)] is a spectrum of connective tissue diseases characterized by micro‐ and macro‐vasculopathy, inflammation and autoimmunity and tissue remodelling that often leads to excessive scarring and fibrosis in both interstitial and vascular compartments. Pre‐clinical investigations and gene association studies have led to improved understanding of the cell and molecular mechanisms underlying disease pathogenesis and to the identification of key molecular candidates that may represent potentially useful disease biomarkers and effective therapeutic targets. Studies on the endothelin (ET) system, pre‐dominantly ET‐1 and the cell surface receptors [type A (ET A )] and type B (ET B )], have provided evidence for an important role of this system in the vascular and fibrotic pathologies in SSc. To date, promising clinical results, utilizing dual/mixed ET receptor antagonism have been obtained in two of the vascular complications associated with SSc, ischaemic digital ulceration and pulmonary arterial hypertension. Evidence suggests that ET‐1 is able to activate and re‐program the functional phenotypes of vascular smooth muscle cells, microvascular pericytes and tissue fibroblasts into pro‐fibrogenic cell populations with myofibroblasts‐like properties. The impact of receptor‐selective, over mixed‐receptor, antagonism has also been studied in vitro with respect to cell differentiation and proliferation, extracellular matrix synthesis, production and deposition and in pathological cellular contraction. However, the complexity of the ET system, potential for receptor cross‐talk, interactions with down‐stream signal transduction cascades, as well as the potent inter‐relationships with other important ligand‐receptor pathways have made in vivo studies difficult to unravel. Moreover, little information is available on the role of the ET system and receptor selectivity in the recruitment and activation of mesenchymal progenitor cells in tissue remodelling and fibrosis or on the early inflammatory response. Here, we discuss the available pre‐clinical evidence for the role of the ET system in tissue repair, scarring and fibrosis, using the connective tissue diseases SSc and model systems of fibrogenesis.