Arterial smooth muscle cell PKD2 (TRPP1) channels control systemic blood pressure

Abstract

Hypertension, a disease that afflicts more than one quarter of the World's population, is a major risk factor for cardiovascular diseases. Blood pressure is determined in part by arterial smooth muscle cells (myocytes) that alter resistance vessel tone. In vivo mechanisms that regulate myocyte contractility to control physiological blood pressure and become pathological during hypertension are poorly understood. Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, although it is unclear if these proteins control physiological blood pressure and can be targeted to alleviate hypertension. Here, we generated the first inducible, smooth muscle‐specific knockout for a TRP channel, namely for PKD2 (TRPP1), to investigate blood pressure regulation by this protein. Data indicate that PKD2 knockout dilates resistance‐size systemic arteries and reduces blood pressure. We show that heterogeneous stimuli activate PKD2 channels in arteries of different organs. Intravascular pressure stimulate PKD2 channels in skeletal muscle arterial myocytes, whereas α1‐adrenergic receptors activate PKD2 channels in myocytes of mesenteric arteries. Regardless of the stimulus or arterial bed, PKD2 current activation in myocytes leads to vasoconstriction. Hypertension is associated with an increase in the abundance of plasma membrane PKD2 channels in systemic arteries. Myocyte‐specific PKD2 knockout caused vasodilation, lowered systemic blood pressure and prevented arterial remodeling during hypertension. In summary, we show that PKD2 channels are activated by distinct vasoconstrictor stimuli in arterial myocytes of different tissues, control physiological systemic blood pressure, are upregulated during hypertension and knockout reduces high blood pressure. These data suggest that targeting of arterial myocyte PKD2 channels could be exploited to control blood pressure and alleviate cardiovascular diseases.Support or Funding InformationThis study was supported by NIH/NHLBI grants HL67061, 133256 and HL137745 to J.H.J, and American Heart Association Scientist Development Grants to S.B and M.D.L.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.