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

Abstract

Occlusive vascular disease is 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 smooth muscle 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 smooth muscle cells have upregulated TRPC1 associated with enhanced calcium entry and cell cycle activity. Neointimal smooth muscle 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 smooth muscle cells that expressed more TRPC1 than the medial layer cells. Veins were organ cultured to allow growth of neointimal smooth muscle cells over a 2-week period. To explore the functional relevance of TRPC1, we used a specific E3-targeted antibody to TRPC1 and chemical blocker 2-aminoethoxydiphenyl borate. Both agents significantly reduced neointimal growth in human vein, as well as calcium entry and proliferation of smooth muscle cells in culture. The data suggest upregulated TRPC1 is a general feature of smooth muscle cells in occlusive vascular disease and that TRPC1 inhibitors have potential as protective agents against human vascular failure.

The non-excitable smooth muscle: Calcium signaling and phenotypic switching during vascular disease

“…In the same study, balloon dilatation of human internal mammary artery showed a similar increase in TRPC1 and TRPC6 mRNA expression 48 h post injury [14]. TRPC1 is upregulated following experimental vascular injury in mice and pigs, and is associated with the conversion of smooth muscle cells from a quiescent to a proliferative phenotype initiating neointimal formation [74]. Upregulation of TRPC1 was associated with enhanced Ca 2+ entry and cell cycle activity.…”

“…Most studies of VSMC phenotypic switching have focused on identification of factors that promote this process (e.g., growths factors and cytokines, oxidative stress, mechanical stress, endothelial factors) or on transcriptional regulation of phenotype-specific genes [70,101,102]. These studies have mainly focused on the loss of contractile proteins with very few reports devoted to the acquisition of proproliferative or pro-migratory proteins such as ion channels and pumps [14,32,74].…”

“…Upregulation of TRPC1 was associated with enhanced Ca 2+ entry and cell cycle activity. The functional relevance of TRPC1 upregulation in neointimal growth was studied in a human saphenous vein organ culture where TRPC1 function was blocked with a specific antibody targeted to its third extracellular loop (E3); this approach significantly inhibited neointimal growth in organ culture as well as calcium entry and VSMC proliferation [74].…”

Endothelin-Induced Sarcoplasmic Reticulum Calcium Depletion Waves in Vascular Smooth Muscle Cells

“…Our findings show that these waves: (1) are due to regenerative CICR by the receptors for IP 3 (IP 3 R), (2) have a marked latency period, (3) are characterized by a transient increase in SR Ca 2+ ([Ca 2+ ] SR ) both at the point of origin and at the wave front, (4) proceed with diminishing velocity, and (5) are arrested by the nuclear envelope. Our quantitative model indicates that the gradual decrease in the velocity of the SR depletion wave, in the absence of external Ca 2+ , results from continuity of the SR luminal network.In VSMCs, Ca 2+ controls multiple functions, including contraction-relaxation, proliferation, migration and apoptosis, in health and disease [5][6][7]. This could be explained by the widely held view that functional selectivity of the Ca 2+ signal is encoded in its spatial and temporal characteristics [8][9][10].…”

“…In VSMCs, Ca 2+ controls multiple functions, including contraction-relaxation, proliferation, migration and apoptosis, in health and disease [5][6][7]. This could be explained by the widely held view that functional selectivity of the Ca 2+ signal is encoded in its spatial and temporal characteristics [8][9][10].…”