Intravascular pressure stimulates arterial smooth muscle cell depolarization, leading to voltage‐dependent Ca2+ channel (Cav1.2) activation and vasoconstriction; a reaction termed the ‘myogenic response’. PKD2 (also termed TRPP1), is a non‐selective cation channel, expression of which has been demonstrated in myocytes of cerebral and mesenteric arteries. Mechanisms that regulate PKD2 activity are unclear. Here, we investigated the regulation of PKD2 surface abundance by intravascular pressure in murine hindlimb arteries using a combination of Western blotting, arterial biotinylation, and pressurized artery myography techniques. We found that PKD2 is primarily plasma membrane‐localized in myocytes of hindlimb arteries. Loss of intravascular pressure due to depressurization lead to PKD2 internalization and lysosomal degradation. In contrast, arterial depressurization did not alter TRPM4, TRPC6, CaV1.2, ANO1, or KV2.1 proteins. Intravascular pressure (80 mmHg) or a bath solution containing 30 mM K+, which depolarizes arteries to physiological membrane potential, prevented PKD2 internalization and degradation. Nimodipine, a voltage‐dependent Ca2+ channel (Cav1.2) blocker, inhibited depolarization‐induced stabilization of PKD2 protein. PKD2 surface protein and myogenic tone were measured in arteries pressurized to either 10 or 80 mmHg. Pressurizing arteries to 80 mmHg prevented the loss of both surface PKD2 and myogenic tone that occurred in arteries pressurized to 10 mmHg. Consistent with a central function of PKD2, myogenic tone was strongly attenuated in hindlimb arteries from conditional, smooth muscle‐specific PKD2 knockout mice. In summary, we show that intravascular pressure promotes PKD2 surface expression in arterial smooth muscle cells through a mechanism involving membrane depolarization and Cav1.2 channel activation, to cause vasoconstriction. Thus, intravascular pressure self‐regulates the myogenic response by controlling PKD2 surface abundance in arterial smooth muscle cells.Support or Funding InformationThis study was supported by NIH/NHLBI grants to J.H.J. and American Heart Association grants to R.H. and S.B.