ENDOTHELINS AS CELL-GROWTH REGULATORS

Endothelins (ETs) were originally identified as a family of potent vas oactive peptides produced by endothelial cells (Yanagisawa et al., 198 8). Subsequent studies have demonstrated the presence of ETs and their receptors in a variety of tissues and cell types where ETs, acting in a paracrine/autocrine manner, were found to exert various biological effects (Gulati and Srimal, 1992; Filep, 1993; Haynes and Webb, 1993; Simonson, 1993; Bauer et al., 1994; Levesque et al., 1994). ETs have b een implicated in a number of human diseases; clinical relevance of ET assay in human medicine is critically examined and seems to be promis ing (Battistini et al., 1993a). At present, the existence of two recep tor subtypes (seven membrane-spanning domains), designated ET(A) and E T(B), has been confirmed. The existence of a third type, ET(C), has al so been reported; however, whether or not it is a variant of the previ ous ones or a new subtype is not clear yet (Masaki et al., 1994). Furt her complexity arises from pharmacological and biological studies (Els hourbagy et al., 1993; Sedo et al., 1993; Sokolovsky, 1994). Interesti ngly, organ ET receptor type composition and thus ET action in some or gans can also be sex dependent (Jouneaux et al., 1994). Growth regulat ory properties of endothelins were reviewed in an excellent paper of B attistini and coworkers (1993b), covering literature up to the start o f 1992. However, in the last three years, new studies have added to ou r knowledge of ETs. Thus, this review will emphasize recent informatio n about endothelins' role in cell proliferation regulation, ET mitogen ic effect signal transduction, and ET functional involvement in comple x cooperations with ''standard'' growth factors and cytokines.