Abstract
Systemic blood pressure is determined, in part, by arterial smooth muscle cells (myocytes). Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, but it is unclear if these proteins control physiological blood pressure and contribute to hypertension in vivo. We generated the first inducible, smooth muscle-specific knockout mice for a TRP channel, namely for PKD2 (TRPP1), to investigate arterial myocyte and blood pressure regulation by this protein. Using this model, we show that intravascular pressure and α1-adrenoceptors activate PKD2 channels in arterial myocytes of different systemic organs. PKD2 channel activation in arterial myocytes leads to an inward Na+ current, membrane depolarization and vasoconstriction. Inducible, smooth muscle cell-specific PKD2 knockout lowers both physiological blood pressure and hypertension and prevents pathological arterial remodeling during hypertension. Thus, arterial myocyte PKD2 controls systemic blood pressure and targeting this TRP channel reduces high blood pressure.
Highlights
Systemic blood pressure is controlled by total peripheral resistance, which is determined by the diameter of small arteries and arterioles
PCR of vasculature in Pkd2fl/fl:myosin heavy polipeptide 11 (Myh11)-cre/ERT2 arteries produced a faint 318 bp band, suggesting that PKD2 is expressed in vascular wall cell types other than myocytes where DNA would not undergo recombination (Figure 1—figure supplement 1)
PKD2 channel activation leads to a inward sodium current (INa) in myocytes, which induces membrane depolarization and vasoconstriction
Summary
Systemic blood pressure is controlled by total peripheral resistance, which is determined by the diameter of small arteries and arterioles. Experiments performed using cultured and non-cultured cells and whole arteries, which contain multiple different cell types, have suggested that approximately thirteen different TRP channels may be expressed in arterial myocytes, including PKD2 ( termed TRPP1), TRPC1, TRPC3-6, TRPV1-4, TRPA1, TRPM4 and TRPM8 (Earley and Brayden, 2015). Our study indicates that PKD2 channels in systemic artery myocytes control physiological blood pressure and are upregulated during hypertension, contributing to the blood pressure elevation
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