Microvascular Permeability in Preeclampsia

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Pre-eclampsia is a multisystem disorder of the second half of pregnancy, characterized by hypertension and pro-teinuria. Although the primary pathology remains unexplained, it appears that abnormal implantation and placental ischemia may be the basis of the disease. The mechanisms by which reduced placental perfusion translates into profound alterations of maternal physiology are still unclear. There is functional, morphological, and biochemical evidence that generalized endothelial dysfunction underlies the clinical manifestations of the disease. Clinical features of the disease, such as edema, proteinuria, and reduced plasma volume, suggest that increased microvascular permeability may play a role in the pathophysiology and the resulting complications of the disease. For example, plasma volume, which is less than normal in pre-eclampsia, correlates positively with birth weight and inversely with disease severity. Edema affecting organs such as the brain, eyes, and lungs increases the morbidity and mortality associated with the disease. The risk of pulmonary edema is significantly greater in pre-eclampsia compared to normal pregnancy and is a major cause of death from the disease.

The reduced plasma volume seen in pre-eclampsia is due to an altered distribution of total extracellular fluid volume (ECFV). Although total ECFV remains unaltered in pregnancies complicated by the disease, redistribution of plasma volume into the interstitial space as a result of increased microvascular permeability occurs, as evidenced by the reduction in the ratio of intravascular to interstitial fluid volumes. Studies of Evans Blue dye disappearance have shown increased microvascular permeability to proteins in pregnancies complicated by pre-eclampsia. The albumin-bound Evans Blue dye disappears faster from the intravascular compartment of women with pre-eclampsia compared to normal pregnant controls. Moreover, the change correlates significantly with the degree of proteinuria and with the level of edema. Since the dye is firmly bound to albumin, the increased permeability implies a reduction in the value of the osmotic reflection coefficient (o), thereby reducing the effective oncotic pressure generated by the plasma proteins.

However, it should be noted that the results of different ways of examining this phenomenon do not give consistent results. For example, although increased microvascular permeability in pre-eclampsia is observed using the Evans Blue dye redistribution technique (confirmed by various investigators), other workers failed to demonstrate any correlation between permeability measured with different methodologies and the degree of proteinuria. Furthermore, there is a poor correlation between plasma volume and microvascular permeability. These results suggest that other components of the Starling equation that govern the movement of fluid across the microvascular interface may also play a role in the observed plasma volume reduction in preeclampsia. It should be noted that the oncotic pressure measured in vitro, where the value of (o) for the examining membrane is 1.0, might differ from the effective (in vivo) oncotic pressure at the microvascular interface, which is influenced by pathophysiological and physicochemical changes at the endothelial interface.

Oncotic Pressure Gradient in Pre-eclampsia

It has been shown that compared to normal pregnancy, plasma albumin concentration and oncotic pressures are reduced by 6 percent and 27 percent in moderate and severe pre-eclampsia, respectively. In moderate pre-eclampsia the reduction in plasma oncotic pressure is compensated for by a similar reduction in interstitial oncotic pressure, so that oncotic pressure gradient and therefore plasma volume remain unchanged. The reduction in interstitial fluid oncotic pressure may be due interstitial protein washout, attributable to increased lymphatic protein transport and/or dilution of preexisting interstitial protein by the increased microvascu-lar filtration of protein-poor fluid. In contrast, in severe pre-eclampsia, the interstitial oncotic pressure increases so that the transcapillary oncotic pressure gradient falls. This increase in interstitial oncotic pressure could be due to reduced capillary pressure (secondary to raised precapillary resistance, for instance), increased microvascular permeability to plasma proteins, or reduced lymphatic flow. It has been noted that interstitial oncotic pressure appears to correlate with the degree of hypertension and the level of proteinuria, as well as with peripheral edema, suggesting that increased microvascular permeability to proteins may be a major contributor to the increase. This may explain the reduced plasma volume and hemoconcentration often observed in severe pre-eclampsia.

Hydrostatic Pressure Gradient in Pre-eclampsia

Interstitial hydrostatic pressure increases in pre-eclampsia, and this may be due to raised interstitial fluid volume as a result of increased microvascular filtration, which is not adequately compensated by increased lymph flow. However, the reported increase in hydrostatic pressure is small and may be attributable to high interstitial tissue compliance. Capillary hydrostatic pressure calculated from other components of the Starling equation increases by 30 percent between the first and third trimester in normal pregnancy, but decreases by 40 percent during the same period in pre-eclampsia. Since capillary pressure is dependent on the values of pre- and postcapillary resistance, the low values may be due to increased precapillary tone from the generalized vasospasm in pregnancies complicated by the disease. However, intravascular pressures at the microvascular interface may be influenced by postcapillary pathophysiological changes.

Endothelial Barrier Function in Pre-eclampsia

Although changes in the oncotic and hydrostatic pressure gradients do occur in pre-eclampsia compared to normal pregnancy, they do not appear adequately to explain the increased fluid flux observed in pregnancies complicated by the disease. Whereas increased microvascular filtration capacity resulting from the generalized endothelial dysfunction of pre-eclampsia may account for the enhanced microvascular permeability, the precise local mechanism(s) remain unexplained. Such mechanisms may include redistribution of endothelial junctional proteins, as well as the effects of circulating permeability factor(s), several of which are elevated in pregnancies complicated by the condition.

Endothelial Junctional Proteins in Pre-eclampsia

There is evidence that the endothelial cell dysfunction known to occur in pre-eclampsia results in redistribution of the endothelial cell junctional proteins: VE-cadherin and occludin. VE-cadherin is an endothelium-specific cadherin that regulates junction organization in endothelial cells and is selectively expressed in all types of endothelial cells. It plays an important role in the organization of lateral endothelial junctions, and its expression is required for the maintenance of normal endothelial barrier function. Occludin is a transmembrane glycoprotein that is found in tight junctions and has a dual role in terms of barrier function. Tight junctions create the primary barriers to solute diffusion through paracellular pathways. They also serve as a barrier between apicolateral and basolateral plasma membrane domains, maintaining cell polarity. VE-cadherin and occluding junctional protein organizations and the permeability of endothelial cell monolayers isolated from human umbilical vein endothelial cells (HUVECs) from both normal pregnant and pre-eclamptic pregnancies have been compared using electron microscopy.

In pre-eclampsia, junctional proteins are disorganized, and in addition, the permeability of the endothelial mono-layer is significantly increased. Furthermore, significant correlation has been observed between the monolayer permeability and junctional protein redistribution. Although the data provided an insight into the molecular basis for increased microvascular permeability, the HUVEC samples used in this study were of fetal origin and may differ functionally from maternal endothelial cells. Thus, although interesting, the observations may not reflect maternal endothelial barrier function.

Circulating Permeability Factors in Pre-eclampsia

The altered junctional protein expression associated with increased microvascular permeability appears to be a consequence of some pathophysiological events that affect endothelial function rather than an inherent endothelial cell defect. Although the main reason for this is given as the reversibility of the adverse changes, it should be remembered that endothelial cells have a slow but significant rate of turnover, so that the "recovery" might reflect cell replacement. Pathological features of pre-eclampsia such as oxida-tive stress, neutrophil activation, and the release of inflammatory cytokines could be responsible for initiating the endothelial barrier dysfunction associated with pregnancies complicated by the disease.

There is evidence that sera from women with pre-eclampsia rather that normal pregnancy increase the permeability of HUVEC monolayers. This suggests that there may be a factor or factors present in the maternal circulation that are responsible for the increased microvascular permeability in pregnancies complicated by the disease. Maternal circulating factors that are elevated in pre-eclampsia and may affect microvascular permeability include vascular endothe-lial growth factor (VEGF), angiopoietins, leptin, proinflammatory cytokines such as tumor necrosis factor-a (TNF-a), and, more recently, neurokinin B. The possible mechanism^) of action of these circulating factors on microvascular permeability are discussed next.

VEGF and Angiopoietin-1

VEGF is a 43- to 46-kDa glycoprotein that serves as a key factor in the maintenance of a confluent, normally functioning vascular endothelium. Physiological levels of VEGF in the serum are pivotal for maintaining vascular endothelial cell homeostasis. VEGF is one of the most potent micro-vascular permeability inducing agents known. Circulating levels are elevated in pre-eclampsia, and this appears to be related to tissue hypoxia associated with the disease. Angiopoietins are vascular endothelial cell-specific growth factors that play an important role, principally during the last stages of the angiogenesis occurring after the induction of new capillaries by VEGF. There is evidence that overexpression of angiopoietin-1 (Ang-1) results in nonleaky vessels by inhibiting the effects of VEGF. Although combined overexpression of VEGF and Ang-1 has been shown to have an additive effect on new vessel formation, this combination results in leak-resistant vessels typical of Ang-1. Furthermore, Ang-1 suppresses VEGF-induced expression of cell adhesion.

Although the role of VEGF in microvascular permeability in the nonpregnant state is well established, its role in microvascular permeability in pregnancies complicated by pre-eclampsia remains to be established. Using scanning electron microscopy, it has been shown that incubation of subcutaneous arteries from women with pre-eclampsia with VEGF increases vascular permeability with disorganization of the vascular endothelium and development of intercellular gaps. In the same study, Ang-1 was shown to reverse the VEGF-induced increase in permeability as well as the development of gap junctions. These observations certainly support the notion that Ang-1 can act as antipermeability factor. However, in a clinical study using venous occlusion plethysmography to measure microvascular filtration capacity as an index of permeability, no correlation was observed between microvascular permeability and plasma concentrations of VEGF. It is therefore possible that the effect of increased VEGF on vascular permeability is suppressed by the presence of other circulating factor(s), such as Ang-1, in pregnancies complicated by pre-eclampsia.

Tumor Necrosis FACTOR-a (TNF-a)

TNF-a is a proinflammatory cytokine and is associated with increased microvascular permeability, for example in sepsis. It appears to do this in studies of nonpregnant women by increasing the permeability coefficient (Lp) of venular endothelial cells. Plasma levels of TNF-a are significantly increased in pre-eclampsia and may play a role in the pathophysiology of the disease. TNF-a released by the ischemic placenta may provide the link between abnormal placenta-tion and maternal endothelial dysfunction. It has also been postulated that the effects of TNF-a may be mediated by oxidative stress. Thus, it would appear that upregulation of TNF-a in pre-eclampsia might provide a mechanism for the increased microvascular permeability seen in this disease. There is indeed evidence of a positive correlation between plasma TNF-a concentrations and microvascular permeability in pre-eclamptic patients, although not in pregnant controls.

Leptin

Leptin, a protein product of the obesity gene, plays an important role in regulation of body weight in the nonpreg-nant state through its receptors in the satiety center of the hypothalamus. Endothelial cells also express leptin receptors. Their activation induces angiogenesis and increases microvascular permeability. It has been suggested that the increased circulating leptin found during pregnancy is of placental origin. Although the functions of leptin in the placenta are not known, in addition to its angiogenic effect it has been suggested that may help to increase the exchange of small molecules between the maternal circulation and the fetus by enhancing convective mechanisms and by the induction and maintenance of increased vascular permeability. Placental expression and circulating levels of leptin are significantly increased in pregnancies complicated by pre-eclampsia. structurally, leptin has been shown to resemble class I cytokines. Moreover, it may regulate placental cytokine production during pregnancy itself.

Neurokinin B

Neurokinin B is a decapeptide of the tachykinin family, a group of neuropeptides that include substance P, a well-established proinflammatory neuropeptide and a potent mediator of increased microvascular permeability. There is evidence that neurokinin B is a potent stimulator of plasma extravasation through two distinct pathways: via activation of NK1 receptors, and via a neurokinin-independent pathway. The human placenta expresses neurokinin B, and plasma concentrations are significantly elevated in pregnancies complicated by pre-eclampsia. It has been suggested that elevated levels may explain edema formation in pre-eclampsia in a manner similar to its effect in causing plasma extravasation in animal studies. Although neurokinin B may provide the candidate permeability factor in pre-eclampsia, edema is not specific to pre-eclampsia and occurs in up to 80 percent of pregnant women.

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