Upregulated TRPC1 Channel in Vascular Injury In Vivo and Its Role in Human Neointimal Hyperplasia

Occlusive vascular diseaseis a widespread abnormality leading to lethal or debilitating outcomes such as myocardial infarction and stroke. It is part of atherosclerosis and is evoked by clinical procedures including angioplasty and grafting of saphenous vein in bypass surgery. A causative factor is the switch in smoothmuscle cells to an invasive and proliferative mode, leading to neointimal hyperplasia. Here we reveal the importance to this process of TRPC1, a homolog of Drosophila transient receptor potential. Using 2 different in vivo models of vascular injury in rodents we show hyperplasic smoothmuscle cells have upregulated TRPC1associated with enhanced calcium entry and cell cycle activity. Neointimal smoothmuscle cells after balloon angioplasty of pig coronary artery also express TRPC1. Furthermore, human vein samples obtained during coronary artery bypass graft surgery commonly exhibit an intimal structure containing smoothmuscle cells that expressed more TRPC1than the medial layer cells. Veins were organ cultured to allow growth of neointimal smoothmuscle cells over a 2-week period. To explore the functional relevance of TRPC1, we used a specific E3-targeted antibody to TRPC1and chemical blocker 2-aminoethoxydiphenyl borate. Both agents significantly reduced neointimal growth in human vein, as well as calcium entry and proliferation of smoothmuscle cells in culture. The data suggest upregulated TRPC1is a general feature of smoothmuscle cells in occlusive vascular diseaseand that TRPC1inhibitors have potential as protective agents against human vascular failure.