Mechanisms of Endothelin-Induced Mitogenesis in Vascular Smooth Muscle

Abstract

The study of signal transduction mechanisms of the endothelin (ET) family of vasoactive peptides is in its infancy compared to the study of growth factor activated pathways. The most proximal mechanisms activated by ETs are well known—activation of phospholipase C-β, and subsequently protein kinase C (PKC), and activation of plasma membrane Ca2+ channels. What is only starting to become clear is how these proximal signaling pathways, which are strikingly different from proximal mechanisms activated by growth factors, culminate in the activation of the same protein serine/threonine kinase cascade that has dominated the research on growth factor signaling over the past several years, the c-Raf-1 cascade. To understand ET-induced mitogenesis it is critical to understand how a G protein-coupled receptor activates this and potentially other kinase cascades, because it is primarily protein kinases that transduce signals from cell surface receptors to the nucleus, thus altering the transcription of genes which lead to the mitogenic response. In this chapter I will first explore the role of the ETs as growth factors and discuss candidate modulators or transducers of the mitogenic signal. Then I will focus on two major areas of ET signalling that putatively play major roles in transducing the mitogenic signal: the c-Raf-1/extracellularsignal regulated kinase (ERK), also known as mitogen-activated protein kinase (MAP) cascade, which is critical to the mitogenic response to growth factors, and activation of nonreceptor tyrosine kinases including Src, the focal adhesion kinase (FAK), and the Janus kinase (Jak) family with their substrates, the STAT (signal transducers and activators of transcription) family of transcription factors. Finally, I will discuss possible roles for other pathways in the mitogenic response to ETs, including phosphoinositide-3 kinases and protein kinase cascades culminating in the activation of other members of the MAP kinase superfamily such as the stress-activated protein kinases (SAPKs) and p38. Because the ETA, but not ETB receptor appears to be primarily responsible for ET signaling in vascular smooth muscle cells (1) much of the work that will be reviewed herein derives from studies in which endothelin-1 (ET-1) was used as agonist in cells which signal primarily via the ETA receptor. Although relatively little is known about signalling triggered by the other ETs acting via the ETB receptor, with the recent discovery of the role of the ETB receptor and ET-3 in megacolon (2,3) and the production of ETB-specific antagonists, this deficiency should soon be corrected.