Microparticles in cardiovascular diseases.

Microparticles are membrane vesicles released from many different cell types. There are two mechanisms that can result in their formation, cell activation and apoptosis. In these two mechanisms, different pathways are involved in microparticle generation. Microparticle generation seems to be a well regulated process. Microparticles vary in size, phospholipid and protein composition. They have a potent pro-inflammatory effect, promote coagulation and affect vascular function. Since these processes are all involved in the pathogenesis of cardiovascular disease and circulating microparticle numbers are altered in many cardiovascular diseases, a role for microparticles in the pathogenesis of cardiovascular diseases is likely. Although hard evidence for a role of microparticles in cardiovascular diseases at present is still only limited, new evidence is accumulating rapidly to support this theory. Elucidation of the microparticle composition and the mechanisms involved in exertion of their effects will supply this evidence and enable us to develop additional intervention strategies for prevention and treatment of cardiovascular diseases.

Endothelial dysfunction in uterine circulation in preeclampsia: can estrogens improve it?

OBJECTIVE: The purpose of this study was to evaluate whether a 3-hour incubation with 17beta-estradiol will enhance blood flow- and bradykinin-mediated dilatation and alter pressure-induced basal tone in myometrial resistance arteries from women with preeclampsia and to evaluate the role of nitric oxide in the responses that were observed. STUDY DESIGN: Blood flow- and bradykinin-mediated dilatation and responses to intraluminal pressure of 60 and 80 mm Hg were compared before and after 3 hours of incubation with 17beta-estradiol (10(-8) mol/L) in isolated myometrial arteries with the pressure myography technique. In separate experiments, the role of nitric oxide on 17beta-estradiol-induced responses was evaluated in the presence of the nitric oxide synthase inhibitor (10(-4) mol/L). Endothelial morphologic condition was evaluated by scanning electron microscopy. RESULTS: Incubation with 17beta-estradiol significantly improved blood flow-mediated dilatation compared with initial blood flow-mediated response in arteries from women with preeclampsia. This effect was nitric oxide mediated, because the nitric oxide synthase inhibitor abolished the response. Arteries from women with preeclampsia demonstrated impaired bradykinin-mediated dilatation compared with that obtained in arteries from normal pregnant women. The 17beta-estradiol had no effect on bradykinin-mediated dilatation in arteries from women with preeclampsia. The enhanced pressure-induced tone at 80 mm Hg compared with the tone that developed at 60 mm Hg in arteries from women with preeclampsia was reduced after incubation with 17beta-estradiol. This reduction was also nitric oxide mediated. Morphologic signs of endothelial dysfunction were evident in arteries from women with preeclampsia. CONCLUSION: The 17beta-estradiol improved impaired blood flow-mediated dilatation and reduced basal tone through a nitric oxide-mediated pathway in isolated myometrial arteries from women with preeclampsia.

Isolated microparticles, but not whole plasma, from women with preeclampsia impair endothelium-dependent relaxation in isolated myometrial arteries from healthy pregnant women.

OBJECTIVE: This study was performed to establish whether microparticles from plasma of women with preeclampsia cause endothelial dysfunction, as described for isolated myometrial arteries in preeclampsia. STUDY DESIGN: Myometrial arteries were isolated from biopsy specimens obtained at cesarean delivery from healthy pregnant women (n = 22) and mounted in a wire myograph. Bradykinin concentration-response curves were obtained before and after 1-hour incubation or after overnight incubation with one of the following preparations of plasma from individual women with preeclampsia (n = 16): Whole plasma, microparticle-free plasma, isolated microparticles resuspended in physiologic saline solution or physiologic saline solution. Overnight incubation was also performed with microparticles isolated from healthy pregnant women (n = 6). One-hour incubation was performed with 2% or 10% solution and overnight incubation with 5% solution. RESULTS: No effect of preeclamptic plasma, with or without microparticles, on bradykinin-mediated relaxation was observed. Overnight, but not 1-hour, incubation with preeclamptic microparticles caused abolishment of bradykinin-mediated relaxation in contrast to healthy pregnant microparticles (P <.005). CONCLUSION: Preeclamptic microparticles, but not healthy pregnant microparticles cause endothelial dysfunction in isolated myometrial arteries from healthy pregnant women after overnight incubation, whereas other preeclamptic plasma constituents protect the endothelium from this effect.

Enhanced coagulation activation in preeclampsia: the role of APC resistance, microparticles and other plasma constituents.

Coagulation activation in pregnancy is further enhanced in preeclampsia. We investigated whether this results from increased thrombin generation by the plasma itself or its cell-derived microparticles. Plasma samples were obtained from preeclamptic, normal pregnant and nonpregnant women (each n = 10). Prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) concentrations were increased in pregnancy and further increased in preeclampsia. In pregnancy and preeclampsia, increased activated protein C resistance occuffed (APC sensitivity ratio: 3.3 +/- 0.8 and 2.5 +/- 0.8, both P <0.001 vs. nonpregnant). In normal pregnant microparticle-free plasma the thrombin generation correlated with TAT (r = 0.84, P = 0.005) and APC resistance correlated with F1+2 (r = 0.68, P = 0.04). In preeclampsia thrombin generation by plasma was increased (P = 0.005), independent of APC resistance. Thrombin generation by microparticles was similar in all groups, although different coagulation activation pathways were utilized, indicating that circulating microparticles are not directly involved in coagulation activation in pregnancy and preeclampsia. In contrast, APC resistance can explain coagulation activation in pregnancy, while enhanced coagulation activation in preeclampsia results, in part, from an increased thrombin generating capacity of plasma independent of APC resistance.

Microparticle subpopulations are increased in preeclampsia: possible involvement in vascular dysfunction?

OBJECTIVE: The purpose of this study was to investigate the cellular origin and numbers of circulating microparticles in normal pregnancy and preeclampsia. STUDY DESIGN: Plasma samples from 10 women with preeclampsia, from 10 normal pregnant women, and from 10 nonpregnant women matched for age and gestation, were analyzed by flow cytometry. RESULTS: The total number of circulating microparticles was unaltered in pregnancy and preeclampsia. The largest portion of microparticles was derived from platelets in all groups. T-suppressor cell microparticle numbers were decreased in normal pregnancy (P =.04). In preeclampsia T-suppressor, T-helper cell, and granulocyte microparticle numbers were increased (P =.008,.008, and.03, respectively). Elastase concentrations were increased in preeclampsia (P =.02) and correlated with granulocyte microparticle numbers (P =.006). Elastase concentrations correlated with systolic and diastolic blood pressure (P =.001 and.003, respectively), and granulocyte microparticle numbers correlated with systolic blood pressure (P =.05). CONCLUSION: Numbers of T-cell and granulocyte microparticles are increased in preeclampsia. Whether these altered microparticle numbers cause vascular dysfunction in preeclampsia or are a consequence of the disease remains to be established.

Resistance artery smooth muscle function in pregnancy and preeclampsia.

OBJECTIVE: The purpose of this study was to investigate whether the altered vascular resistance in pregnancy and preeclampsia results from alterations in intrinsic vascular smooth muscle properties or from external influences on vascular smooth muscle function. STUDY DESIGN: We studied subcutaneous resistance arteries from women with preeclampsia, from normal pregnant women, and from nonpregnant women, that were obtained during cesarean delivery or gynecologic surgical procedures, in a pressure myograph. Arteries were denervated, and smooth muscle cells were loaded with calcium indicator fura-2. Contractile properties were tested in physiologic saline solution and during potassium- and norepinephrine-induced constriction at various pressures. In addition, endothelial function was assessed. Intracellular calcium and tone were measured continuously. RESULTS: No significant differences in basal tone, constrictor, and myogenic responses were found between groups. Contractile element calcium sensitivity was significantly increased in women with preeclampsia. Norepinephrine caused an increase in calcium sensitivity in all groups. CONCLUSION: Vascular smooth muscle calcium sensitivity is increased in preeclampsia.