Microvascular control mechanisms in copper deficiency

Dietary copper deficiency has long been associated with exaggerated inflammatory responses in both humans and experimental animals. However, the mechanisms for this increased response are not understood. By using the rat cremaster muscle microcirculatory model as a window to the in vivo microcirculation, we have identified and studied three functional changes occurring in the microcirculation that operate during the inflammatory response and appear to be copper-dependent. First, we documented an increased postcapillary venule leakage of protein in response to histamine released by mass cells in copper-deficient rats. This response appears to be the result of increased numbers of mast cells and thereby increased available histamine. The second microvascular change we noted in copper deficiency is that there is decreased in vivo thrombogenesis with a resulting prolonged bleeding time. Additionally, in in vitro studies platelet-endothelial cell adhesion is diminished and the platelet concentration of the adhesion molecule von Willebrand Factor (vWF) is reduced. We propose that reduced vWF-mediated platelet adhesion accounts for the depressed thrombogenesis in copper deficiency. The third difference we found is that nitric oxide-mediated arteriole vasodilation is compromised, which may lead to increased peripheral vascular resistance. This functional deficit to NO can be reversed by the addition of Cu, Zn-SOD. This suggests that it may result from increased scavenging of NO by O-2(-) during copper deprivation. These observations demonstrate that dietary copper has several important functional roles in microvascular control mechanisms affecting inflammation, microhemostasis, and resistance to blood flow. (C) 1996 Wiley-Liss, Inc.