Reference : Regulation of vascular tone in animals overexpressing the sarcolemmal calcium pump.
Scientific journals : Article
Human health sciences : Cardiovascular & respiratory systems
Regulation of vascular tone in animals overexpressing the sarcolemmal calcium pump.
Schuh, Kai [> >]
Quaschning, Thomas [> >]
Knauer, Sebastian [> >]
Hu, Kai [> >]
Kocak, Serkan [> >]
Roethlein, Nicola [> >]
Neyses, Ludwig mailto [University of Luxembourg > Research Office]
The Journal of biological chemistry
Yes (verified by ORBilu)
United States
[en] Acetylcholine/pharmacology ; Animals ; Aorta/drug effects ; Blood Pressure ; Calcium/metabolism ; Calcium-Transporting ATPases/metabolism ; Calmodulin/metabolism ; Cation Transport Proteins ; Cytosol/metabolism ; Dose-Response Relationship, Drug ; Hemodynamics ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Models, Genetic ; Muscle, Smooth/metabolism ; NG-Nitroarginine Methyl Ester/pharmacology ; Nitric Oxide Synthase/antagonists & inhibitors ; Nitroprusside/pharmacology ; Plasma Membrane Calcium-Transporting ATPases ; Potassium Chloride/pharmacology ; Promoter Regions, Genetic ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sarcolemma/metabolism ; Time Factors ; Tissue Distribution ; Transgenes ; Vasodilator Agents/pharmacology
[en] The mechanisms governing vascular smooth muscle tone are incompletely understood. In particular, the role of the sarcolemmal calcium pump PMCA (plasma membrane calmodulin-dependent calcium ATPase), which extrudes Ca2+ from the cytosol, and its importance compared with the sodium/calcium exchanger remain speculative. To test whether the PMCA is a regulator of vascular tone, we generated transgenic mice overexpressing the human PMCA4b under control of the arterial smooth muscle-specific SM22alpha promoter. This resulted in an elevated systolic blood pressure compared with littermate controls. In PMCA-overexpressing mice, endothelium-dependent relaxation of norepinephrine-preconstricted aortic rings to acetylcholine did not differ from wild type controls (76 +/- 8% versus 79 +/- 8% of maximum relaxation; n = 12, n.s.). De-endothelialized aortas of transgenic mice exhibited stronger maximum contraction to KCl (100 mmol/liter) compared with controls (86 +/- 6% versus 68 +/- 7% of reference KCl contraction at the beginning of the experiment; p <0.05). Preincubation of de-endothelialized vessels with the nitric oxide synthase (NOS) inhibitor l-NAME (l-N(G)-nitroarginine methyl ester) (10-5 mol/liter) resulted in a stronger contraction to KCl (p <0.05 versus without l-NAME), thus unmasking vasodilatory effects of inherent NO production. Maximum contraction to KCl after preincubation with l-NAME did not differ between PMCA mice and controls. In analogy to the results in PMCA-overexpressing mice, contractions of de-endothelialized aortas of neuronal NOS-deficient mice to KCl were significantly increased compared with controls (151 +/- 5% versus 131 +/- 6% of reference KCl contraction; p <0.05). In conclusion, our data suggest a model in which the sarcolemmal Ca2+ pump down-regulates activity of the vascular smooth muscle Ca2+/calmodulin-dependent neuronal NOS by a functionally relevant interaction. Therefore, the PMCA represents a novel regulator of vascular tone.

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