Systemic Blood Pressure Regulation by Vascular Ion Channels
Systemic blood pressure is regulated by the diameter of small arteries and arterioles. Arterial smooth muscle cell contraction leads to vasoconstriction that increases systemic blood pressure, whereas smooth muscle cell relaxation decreases blood pressure. Artery membrane potential (voltage) is a primary determinant of contractility. Depolarization activates voltage-dependent calcium channels in smooth muscle cells, leading to an increase in intracellular calcium concentration and vasoconstriction. In contrast, hyperpolarization results in vasodilation. As ion channels regulate both artery membrane potential and calcium influx, one of our goals is to identify channels that regulate systemic blood pressure. We have recently investigated blood pressure regulation by smooth muscle cell PKD2 channels, proteins that are also known as transient receptor potential polycystin 1 (TRPP1) channels. Our study demonstrated that PKD2 present in arterial smooth muscle cells regulates systemic blood pressure and targeting this channel reduces hypertension, which is a pathological elevation in blood pressure.
Smooth muscle-specific knock out of PKD2 channels reduces systemic blood pressure.
Ion Channel Trafficking and Functional Significance
Another major goal of the laboratory is to study physiological functions of ion channel trafficking in vascular wall cell types. Recently, we published several papers that investigated physiological stimuli that regulate trafficking of both the alpha and β1 subunits of the large-conductance calcium-activated potassium (BK) channel in arterial smooth muscle cells, mechanisms involved and the functional effects of such signaling on contractility. These studies also demonstrated that hypertension is associated with attenuated trafficking of the β1 subunit, which leads to vasoconstriction. We also described that intravascular pressure regulates the surface abundance of Kv1.5 channels in arterial smooth muscle cells to control contractility. Signaling mechanisms we identified that are involved in regulating the surface abundance of these ion channels are summarized below.
Mechanisms we described that regulate BK channel surface abundance in arterial smooth muscle cells
Kv1.5 channel trafficking in arterial smooth muscle cells
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Fluorescence labeling of an arterial section validating a biotnylation
technique we use in our studies to measure surface proteins |
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