Abstract
In the endothelium, ATP-sensitive potassium (KATP) channels are thought to couple cellular metabolism with membrane excitability, calcium entry, and endothelial mediator release. We hypothesized that endothelial KATP channels have a broad role protecting against high blood pressure and atherosclerosis. Endothelial-specific Kir6.1 KO mice (eKO) and eKO mice on an apolipoprotein E KO background were generated (A-eKO) to investigate the role of KATP channels in the endothelium. Basal blood pressure was not elevated in eKO mice. However, when challenged with a high-salt diet and the eNOS inhibitor L-NAME, eKO mice became more hypertensive than their littermate controls. In aorta, NO release at least partly contributes to the endothelium-dependent vasorelaxation induced by pinacidil. In A-eKO mice atherosclerotic plaque density was significantly greater than in their littermate controls when challenged with a high-fat diet, particularly in the aortic arch region. Levels of endothelial dysfunction markers were higher in eKO compared with WT mice; however, these were not significant for A-eKO mice compared with their littermate controls. Furthermore, decreased vascular reactivity was observed in the mesenteric arteries of A-eKO mice, but not in aorta when on a high-fat diet. Our data support a role for endothelial Kir6.1-containing KATP channels in the endothelial protection against environmental stressors: the maintenance of blood pressure homeostasis in response to high salt and endothelial integrity when challenged with a high-fat diet.
Highlights
The absence of Kir6.1 in vascular smooth muscle (VSM) leads to hypertensive mice, but the hypertension is not as pronounced as in mice with global deletion of Kir6.1.2 To examine the possible contribution of endothelial Kir6.1 in Blood Pressure (BP) regulation, we used continuous telemetric monitoring in conscious 8- to 12-week-old wildtype and Endothelial-specific Kir6.1 KO mice (eKO) mice
There was no difference in prediet SBP and DBP between wildtype and eKO (Day: SBP/DBP, 118.7/90.1±1.6/2.7 mm Hg, night: SBP/DBP, 129.4/99.8±2.3/3.5 mm Hg) mice suggesting KATP channels in the endothelium do not contribute significantly to basal
To investigate if endothelial KATP channels containing Kir6.1 play more of a role in BP regulation when challenged, we put both groups of mice on a diet with L-NAME (5 mg/10 mL of drinking water) and a high salt (HS) chow (8% NaCI) over a period of 4 weeks
Summary
When challenged with a high-salt diet and the eNOS inhibitor L-NAME, eKO mice became more hypertensive than their littermate controls. In A-eKO mice atherosclerotic plaque density was significantly greater than in their littermate controls when challenged with a high-fat diet, in the aortic arch region. Decreased vascular reactivity was observed in the mesenteric arteries of A-eKO mice, but not in aorta when on a high-fat diet. Are hypertensive, but they did not fully recapitulate the global KO phenotype suggesting the involvement of other cellular populations of KATP channels.[2] It is known that K+ currents can influence endothelial function by hyperpolarizing the cell, promoting Ca2+ entry and leading to the release of vasoactive mediators.[11] K channels have been shown to be expressed in vascular endothelial cells (ECs) and. Ca2+ entry into ECs in response to KATP channel activation was eliminated and the response of the coronary circulation to hypoxia was compromised.[5]
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