Myocardial Blood Flow Control by Oxygen Sensing Vascular Kvβ Proteins

Abstract

Rationale: Voltage-gated potassium (Kv) channels in vascular smooth muscle are essential for coupling myocardial blood flow (MBF) with the metabolic demand of the heart. These channels consist of a transmembrane pore domain that associates with auxiliary Kv beta (voltage-gated potassium channel beta)1 and Kv beta 2 proteins, which differentially regulate Kv function in excitable cells. Nonetheless, the physiological role of Kv beta proteins in regulating vascular tone and metabolic hyperemia in the heart remains unknown. Objective: To test the hypothesis that Kv beta proteins confer oxygen sensitivity to vascular tone and are required for regulating blood flow in the heart. Methods and Results: Mice lacking Kv beta 2 subunits exhibited suppressed MBF, impaired cardiac contractile performance, and failed to maintain elevated arterial blood pressure in response to catecholamine-induced stress. In contrast, ablation of Kv beta 1.1 reduced cardiac workload, modestly elevated MBF, and preserved cardiac function during stress compared with wild-type mice. Coronary arteries isolated from Kv beta 2(-/-), but not Kv beta 1.1(-/-), mice had severely blunted vasodilation to hypoxia when compared with arteries from wild-type mice. Moreover, vasodilation of small diameter coronary and mesenteric arteries due to L-lactate, a biochemical marker of reduced tissue oxygenation and anaerobic metabolism, was significantly attenuated in vessels isolated from Kv beta 2(-/-) mice. Inducible enhancement of the Kv beta 1:Kv beta 2 ratio in Kv1 channels of arterial smooth muscle abolished L-lactate-induced vasodilation and suppressed the relationship between MBF and cardiac workload. Conclusions: The Kv beta proteins differentially regulate vascular tone and MBF, whereby Kv beta 2 promotes, and Kv beta 1.1 inhibits oxygen-dependent vasodilation and augments blood flow upon heightened metabolic demand.