Dual action of ET-1 on mesenchymal cell types. Shown are key activities of endothelin (ET)-1 on endothelial cells, vascular smooth muscle cells (vSMCs) and fibroblasts. Rapid endothelin-mediated responses include the modulation of calcium concentration and influx, levels of nitric oxide (NO) and cGMP, and the associated contractile response in order to regulate vascular tone. Slower more adaptive responses include the activation of transcriptional programmes to effect mesenchymal cell transition and differentiation, and extracellular matrix (ECM) production resulting in tissue remodelling. DAG, diacylglycerol; ETA/BR, endothelin receptor subtype A/B receptor; IP3, inositol trisphosphate; MAPK, mitogen-activated protein kinase; PIP, phosphatidylinositol phosphate; PKB, protein kinase B; PKC, protein kinase C; PLC, phospholipase C.