Several important genes that are involved in tissue remodeling and angiogenesis are switched on by virtue of CRE response elements in their promoters. Endothelin (ET) is an important vasoactive mediator that plays roles in vascular remodelling and angiogenesis, by activating 7 transmembrane G protein-coupled receptors (GPCR). Here I will describe studies carried out in our lab characterising the mechanisms ET-1 uses to regulate CRE-dependent remodeling genes in pulmonary vascular smooth muscle cells. We found that ET-1 activated several CRE response genes in vascular smooth muscle cells through two pathways. The first was an autocrine loop involving cPLA2, arachidonic acid release, COX-2-dependent PGI(2) synthesis, and IP receptor-linked elevation of cAMP leading to CRE transcription activation. The second involved a calcium-dependent, COX-2 independent, pathway involving calcium influx through T type voltage-dependent calcium channels. These studies give important insights into the upstream signaling mechanisms used by G protein-coupled receptor-linked mediators such as ET-1, to activate CRE response genes involved in angiogenesis and vascular remodelling.