Pressure-induced constriction of the middle cerebral artery is abolished in TrpC6 knockout mice.

: Pressure-induced constriction (PIC) is an inherent response of small arteries and arterioles in which increases in intraluminal pressure evoke vasoconstriction. It is a critical mechanism of blood flow autoregulation in the kidney and brain. Degenerin (Deg) and transient receptor potential (Trp) protein families have been implicated in transduction of PIC because of evolutionary links to mechanosensing in the nematode and fly. While TrpC6 has been suggested to contribute to PIC signaling, direct supporting evidence is contradictory. Therefore, the aim of this study was to determine the importance of TrpC6 in PIC signaling using a mouse model lacking TrpC6. We evaluated graded pressure (20-90 mm Hg), depolarization- (4-80 mM KCl) and adrenergic receptor- (phenylephrine, PE 10-7-10-4 M) mediated constriction of isolated middle cerebral artery (MCA) segments from 9 week old male wild-type (TrpC6+/+, n=7) and homozygous null (TrpC6-/-, n=9) TrpC6 mice. Isolated MCA segments were pressurized using pressure myography. Vasoconstrictor responses to KCl and PE were identical in TrpC6-/- and TrpC6+/+ mice. In contrast, PIC responses were totally abolished in TrpC6 -/- mice. At 90 mm Hg, the calculated myogenic tone was -0.8±0.5 vs 10.7±1.7%, p=0.0002, in TrpC6-/- and TrpC6+/+ mice, respectively. Additionally, there were no changes in mechanical properties of circumferential wall strain and stress; or morphological properties of wall thickness and wall-to-lumen ratio at 50 mm Hg between TrpPC6-/- and TrpC6+/+ mice. Although these results demonstrate that TrpC6 is critical for the integrated PIC response, they do not identify if TrpC6 acts as a mechanosensor or a downstream signaling component.