Abstract 15824: Microvascular Endothelial Kir2.1 Channels Play Important Role in Flow-Induced Dilation During Hypertension in Humans

Abstract

Hypertension is associated with decreased endothelial function through reduced contributions of NO. Our recent study discovered that flow-induced generation of NO in resistance arteries of mice and humans, and flow-induced vasodilation (FIV), a hallmark of the endothelial response to flow, critically depend 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 in peripheral resistance arteries of humans with hypertension. We measured microvascular function in vessels extracted from subcutaneous fat biopsies isolated from 28 subjects: normotensive (n=19; 30.6±4.4yo; systolic blood pressure-SBP: 115.2±5.7mmHg; diastolic blood pressure-DBP: 75.3±11.3mmHg) and hypertensive (n=9; 50±5.2yo; SBP: 147.1±6.1 mmHg; DBP: 93.1±16.8mmHg). Consistent with previous studies, we find that FIV is impaired in hypertensive subjects as demonstrated by a significant reduction in dilation when compared to the normotensive group. Furthermore, our data suggest that the impairment of FIV in this cohort can be partially attributed to a Kir-dependent vasodilation. Specifically, we show that blocking Kir channels with a specific inhibitor, ML133, or functionally downregulating with endothelial-specific adenoviral vector containing dominant-negative Kir2.1 (dnKir2.1) result in significant decrease in FIV in normotensive subjects and smaller effect in hypertensive patients. The Kir2.1-dependent vasodilation was negatively correlated to both SBP and DBP indicating that Kir contribution reduces as blood pressure increases. In addition, we show that exposing normotensive vessels to acute high pressure, which is known to impair FIV, results in loss of Kir channel contribution, as high-pressure impairs vasodilation in normotensive vessels but no effect is seen when these vessels were incubated with dnKir2.1. Overexpressing WTKir2.1 in endothelium resulted in some improvement in vasodilation in arteries from all participants, with a greater recovery in hypertensive patients. Our data suggest that hypertension-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension.