Preventing stenosis by local inhibition of KCa3.1: a finger on the phenotypic switch.

The sources of genetic alterations that underlie phenotypic switching of vascular smooth muscle cells (VSMCs) during stenosis have recently been the subject of intense study. It is becoming increasingly clear that transcriptional control of ion channels plays an important role not only in expression of the differentiated phenotype, but also in the development and maintenance of the proliferative phenotype (see reviews1,2). Functional expression of voltage-dependent calcium channels (VDCC) and large-conductance Ca -activated K channels (BKCa) is known to be necessary for the maintenance of vascular smooth muscle cell (VSMC) differentiation.3–6 More recently, upregulation of the intermediateconductance Ca -activated K channel, KCa3.1 (IKCa1, encoded by KCNN4) and store-operated Ca channels such as TRPC (transient receptor potential) have been linked to the proliferative phenotype.7–9 Moreover, selective inhibition of KCa3.1 channels using TRAM-34 has been shown to inhibit growth factor–mediated proliferation of VSMCs and to prevent the development of restenosis.10 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Tharp and colleagues contribute to this accumulating evidence through their discovery that local delivery of TRAM-34 via balloon catheter prevents phenotypic switching of coronary artery VSMCs and limits subsequent restenosis. Their findings encourage further investigation of TRAM-34 as a therapy for the prevention of angioplasty-induced restenosis and provide a means for selective delivery that may prevent untoward side-effects associated with systemic administration of TRAM-34. Although the significant players in phenotypic switching are becoming more apparent, many questions remain with respect to how the altered array of ion channels is translated into signals affecting the cell proliferation machinery.