| Autor: |
Do Couto NF; Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, United States., Fancher I; Kinesiology and Applied Physiology, University of Delaware, Newark, DE, United States., Granados ST; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States., Cavalcante-Silva J; Department of Kinesiology and Nutrition, University of Illinois at Chicago, United States., Beverley KM; 1Division of Pulmonary, Critical Care, Allergy and Sleep, University of Illinois at Chicago, United States., Ahn SJ; Medicine, Div. Pulmonary, Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, CHICAGO, Illinois, United States., Hwang CL; Kinesiology, The University of Texas at Arlington, Arlington, TX, United States., Phillips SA; Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, Illinois, Chicago, IL, United States., Levitan I; Medicine, University of Illinois at Chicago, Chicago, IL, United States. |
| Abstrakt: |
Hypertension is associated with decreased endothelial function through reduced contributions of NO. We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly-rectifying K + channels (Kir2.1). The goal of this study was to establish whether these channels contribute to the impairment of endothelial function, measured by flow-induced vasodilation (FIV) in peripheral resistance arteries of humans with hypertension. We measured FIV in vessels isolated from subcutaneous fat biopsies from normotensive (n=19; SBP: 115±27mmHg; DBP: 75.3±5.7mmHg) and hypertensive subjects (n=13; SBP: 146.1±15.2 mmHg; DBP: 94.4±6.9mmHg). We find that FIV is impaired in hypertensive adults as demonstrated by a significant reduction in FIV when compared to the normotensive adults, which is partially attributed to a reduction in Kir2.1-dependent vasodilation. Specifically, we show that pharmacologically inhibiting Kir2.1 or functionally downregulating Kir2.1 with endothelial-specific adenoviral vector dnKir2.1 result in a significant reduction in FIV in normotensive subjects but with a smaller effect in hypertensive adults. The Kir2.1-dependent vasodilation was negatively correlated to SBP and DBP, indicating that Kir2.1 contribution to FIV decreases as blood pressure increases. Furthermore, exposing vessels from normotensive adults to acute high-pressure results in loss of Kir2.1 contribution, as high-pressure impairs vasodilation. No effect is seen when these vessels were incubated with dnKir2.1. Overexpressing wtKir2.1 in the endothelium resulted in some improvement in vasodilation in arteries from all participants, with a greater recovery in hypertensive adults. Our data suggest that high pressure-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension. |
