In 1910, James Herrick made the first report of a case of sickle cell anemia.1 He described thin, elongated, sickleshaped, and crescent-shaped red blood corpuscles. Soon afterward, the observation of sickle cells in the asymptomatic father of a sickle cell anemia patient raised the possibility of an inherited disorder.2 The distinction between symptomatic sickle cell anemia and the asymptomatic sickle cell trait was established in 1933.3 The difference between normal hemoglobin (HbAA) and sickle hemoglobin (HbSS) was recognized in 1959 to be the substitution of a valine residue for a glutamic acid in the -chain amino terminus.4 Patients who have the sickle cell trait are heterozygotes (HbAS), having an abnormal, as well as a normal, -globin gene. In sickle cell anemia, sickling may start at an oxygen saturation as high as 85%, while in the trait the desaturation has to be more severe before sickling is induced. Sickling leading to vaso-occlusion and infarction occurs in many organs but was first described in the lungs.5 Initially it was thought that deformation and increased rigidity of the erythrocytes, related to polymerization of HbSS, was sufficient to cause mechanical obstruction. However, the work of Hebbel et al6,7 focused attention on erythrocyte adherence to the endothelium as a mechanism promoting microvascular occlusion. A key observation in this regard is that sickle erythrocytes adhere more readily to microvascular endothelium than to endothelium from conduit vessels.8 If endothelial cells circulating in the blood can be taken as representative of the sedentary population, the endothelium is activated in sickle cell patients, whether in steady state or in an acute crisis.9 This is shown by expression of the adhesion molecules, ICAM-1, VCAM-1, E-selectin, and P-selectin. More recent work has implicated inflammation as a factor in the pathogenesis of vaso-occlusive crises.10 An increased leukocyte count is an independent risk factor for such episodes,11 and activated neutrophils have been demonstrated to increase retention of sickle erythrocytes in the lung.12 A two-stage model has been proposed, comprising increased adhesion of cells to the endothelium and subsequent mechanical obstruction.13 Although many signaling molecules are involved in cell adhesion, thrombin plays a major role in the chronic inflammation seen in sickle cell disease and particularly in endothelial cell activation.14 Human umbilical vein endothelial cells (HUVECs) exposed to thrombin in vitro show increased adhesivity for sickle cells, while at the same time demonstrating significant interendothelial cell gap formation. Thrombin, by stimulating G protein (Gq)– coupled protease-activated receptors (PARs), increases cellular diacylglycerol (DAG) and inositol trisphosphate (IP3), the latter causing calcium release from the sarcoplasmic and endoplasmic reticulum (SER) (see Figure). Increased DAG and depletion of the SER stores activate store-operated channels (SOCs) (in the plasmalemma) permeable to calcium, triggering further entry of calcium into the cell, activation of myosin light chain kinase (MLCK), and thus cellular contraction. Endothelial cell contraction results in the formation of gaps between cells in the endothelium. This gap formation is enhanced by a decrease in cyclic adenosine monophosphate (cAMP). cAMP is the crucial signal that normally promotes interendothelial cell adhesion. The two second messengers, calcium and cAMP, while responsible for contraction and adhesion, respectively, influence each other in the endothelium. On the one hand, SOCs colocalize with calcium-sensitive adenylate cyclases and the increased calcium entry through SOCs decreases cellular cAMP levels, partly by inhibiting type 6 adenylate cyclases.15 On the other hand, cAMP inactivates MLCK and consequently inhibits contraction. In addition to intracellular calcium, thrombin may enhance gap formation through calcium-independent proteolytic pathways.16 The lung microvasculature arises through vasculogenesis while angiogenesis gives rise to the macrocirculation.17 As a consequence, endothelial cells in the adult lung retain different phenotypes: macrovascular endothelial cells produce more nitric oxide than their microvascular counterparts18; activation of SOCs and a rise in cytosolic calcium cause leaks in the macrovasculature barrier leaving the microvasculature relatively unscathed. Although both pulmonary artery endothelial cells (PAECs) and pulmonary microvasculature endothelial cells (PMVECs) possess SOCs, stimulation of calcium entry through SOCs results in a differential effect in PAECs versus PMVECs. Whereas thapsigargin (a blocker of the SER calcium ATPase and therefore an activator of SOCs) induces shape change and gap formation in PAECs, PMVECs appear resistant to such perturbations. This difference in the effect of calcium entry has been attributed to the tighter regulation of cAMP levels in PMVECs.19 Finally, while PMVECs have been observed to have a resting membrane potential centered at 22 mV, PAECs have a bimodal distribution of resting The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology (E.K.W.), Veterans Affairs Medical Center, Minneapolis, Minn; Department of Medicine (A.V., E.K.W.), University of Minnesota, Minneapolis, Minn. Correspondence to E.K. Weir, MD, Cardiology (111 C), Veterans Affairs Medical Center, One Veterans Drive, Minneapolis, MN 55417. E-mail email@example.com (Circ Res. 2003;93:274-276.) © 2003 American Heart Association, Inc.
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