Ceramide Signaling in the Coronary Microcirculation
A Double-Edged Sword?
Under basal conditions, ≈90% of the resistance to blood flow in the heart occurs in the small arteries and arterioles that make up the coronary microcirculation.1 Microvascular resistance is primarily determined by vessel density and lumen diameter. The latter is highly dynamic in the healthy heart and facilitates large changes in flow to meet increases in myocardial oxygen consumption during stress. Variations in the vascular tone of coronary microvessels results from vasodilator and vasoconstrictor signals that arise in response to physical forces, neurohormonal, and endothelium-derived substances, as well as metabolic mediators released from cardiac myocytes. Of these, vasodilation from increased shear stress or flow-induced dilation provides an important means of communication among various segments of the vasculature to regulate changes in local perfusion more accurately.2 An increasing number of studies have demonstrated that coronary microvascular dysfunction can contribute to precipitating myocardial ischemia and ventricular dysfunction in the absence of coronary artery disease (CAD).3,4 Of equal importance, impaired flow-induced responses predict cardiovascular events in patients with established cardiovascular disease, as well as in asymptomatic subjects.5
Article, see p 525
Although flow-induced dilation requires an intact endothelium, the biochemical mediators of dilation vary by organ, species, vessel size, age, and disease status. For example, in juvenile porcine coronary resistance vessels, nitric oxide (NO) mediates flow-induced dilation,6 yet flow-induced dilation is mediated by a hyperpolarizing factor in epicardial conduit arteries.7 In humans, prostaglandins mediate flow-induced dilation of coronary arterioles from children,2 whereas NO is the primary mediator of flow-induced dilation in normal adults. The presence of CAD or cardiovascular risk factors increases oxidative stress, reduces NO bioavailability, and diminishes the role of NO.8 Despite this, flow-induced dilation in humans can be maintained by mechanisms that compensate for the loss of NO. Miura et …