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Disruption of K(2P)6.1 produces vascular dysfunction and hypertension in mice
Eric E Lloyd1, Randy F Crossland, Sharon C Phillips
1Department of Anesthesiology, Baylor College of Medicine, Houston, TX 77030, USA.
Insights
The two-pore domain potassium channel K(2P)6.1 deficiency increases blood pressure and arterial contraction. This vascular dysfunction is linked to smooth muscle cell depolarization and heightened rho kinase activity.
Area of Science:
- Cardiovascular Physiology
- Ion Channel Function
- Vascular Biology
Background:
- The two-pore domain potassium channel K(2P)6.1 is abundant in the vasculature, but its physiological role remains unclear.
- Understanding K(2P)6.1 function is crucial for elucidating mechanisms of vascular regulation and disease.
Purpose of the Study:
- To investigate the role of K(2P)6.1 in regulating systemic blood pressure.
- To determine K(2P)6.1's impact on arterial contractility, vascular smooth muscle cell (VSMC) migration, proliferation, and volume regulation.
Main Methods:
- Generation of K(2P)6.1 knockout (KO) mice by deleting exon 1 of Kcnk6.
- Measurement of mean arterial blood pressure in anesthetized and awake KO and wild-type mice.
- Assessment of VSMC resting membrane potential and arterial contractile responses to various stimuli (KCl, BAY K 8644, U46619) in isolated aortic segments.
- Evaluation of L-type calcium channel currents and the effects of rho kinase inhibition (Y27632).
Main Results:
- KO mice exhibited significantly elevated mean arterial blood pressure compared to wild-type littermates.
- VSMCs from KO mice showed membrane depolarization and enhanced contractile responses to KCl and BAY K 8644.
- Aortic segments from KO mice displayed increased contraction to U46619, which was attenuated by Y27632.
- No significant differences were observed in L-type calcium channel current density, VSMC migration, proliferation, or volume regulation.
Conclusions:
- K(2P)6.1 deficiency leads to vascular dysfunction and hypertension.
- The underlying mechanisms involve VSMC depolarization and increased rho kinase activity.
- K(2P)6.1 does not appear to play a significant role in VSMC migration, proliferation, or volume regulation.
Abstract:
K(2P)6.1, a member of the 2-pore domain K channel family, is highly expressed in the vascular system; however, its function is unknown. We tested the following hypotheses. K(2P)6.1 regulates the following: (1) systemic blood pressure; (2) the contractile state of arteries; (3) vascular smooth muscle cell migration; (4) proliferation; and/or (5) volume regulation. Mice lacking K(2P)6.1 (KO) were generated by deleting exon 1 of Kcnk6. Mean arterial blood pressure in both anesthetized and awake KO mice was increased by 17±2 and 26±3 mm Hg, respectively (P<0.05). The resting membrane potential in freshly dispersed vascular smooth muscle cells was depolarized by 17±2 mV in the KO compared with wild-type littermates (P<0.05). The contractile responses to KCl (P<0.05) and BAY K 8644 (P<0.01), an activator of L-type calcium channels, were enhanced in isolated segments of aorta from KO mice. However, there was no difference in the current density of L-type calcium channels. Responses to U46619, an agent that activates rho kinase, showed an enhanced contraction in aorta from KO mice (P<0.001). The BAY K 8644-mediated increase in contraction was decreased to wild-type levels when treated with Y27632, a rho kinase inhibitor, (P<0.05). K(2P)6.1 does not appear to be involved with migration, proliferation, or volume regulation in cultured vascular smooth muscle cells. We conclude that K(2P)6.1 deficiency induces vascular dysfunction and hypertension through a mechanism that may involve smooth muscle cell depolarization and enhanced rho kinase activity.
