Cerebrovascular Function in Pregnancy and Eclampsia
2007; Lippincott Williams & Wilkins; Volume: 50; Issue: 1 Linguagem: Inglês
10.1161/hypertensionaha.106.079442
ISSN1524-4563
Autores Tópico(s)Moyamoya disease diagnosis and treatment
ResumoHomeHypertensionVol. 50, No. 1Cerebrovascular Function in Pregnancy and Eclampsia Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBCerebrovascular Function in Pregnancy and Eclampsia Marilyn J. Cipolla Marilyn J. CipollaMarilyn J. Cipolla From the Departments of Neurology, Obstetrics and Gynecology, and Pharmacology, University of Vermont College of Medicine, Burlington. Originally published4 Jun 2007https://doi.org/10.1161/HYPERTENSIONAHA.106.079442Hypertension. 2007;50:14–24Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 4, 2007: Previous Version 1 Hypertension is one of the most common medical complications of pregnancy that affects both fetal and maternal health and is often life threatening.1,2 Multiple maternal organs are affected by hypertension in pregnancy, including the brain in the form of eclampsia.1–4 Eclampsia is a leading cause of maternal death, with classic neurologic symptoms that include headaches, nausea, vomiting, cortical blindness, coma, and convulsions.5–9 Although numerous organs are affected by hypertension in pregnancy, cerebrovascular involvement is the direct mechanism of death in ≈40% of patients.6,7 The major cerebrovascular changes in eclampsia have been shown to be similar to those described for hypertensive encephalopathy, including loss of cerebral blood flow (CBF) autoregulation, hyperperfusion, and edema.8–12 In support of this concept, clinical and neuroimaging findings during eclampsia are consistent with edema, which is thought to result from a rapid rise in blood pressure that causes forced dilatation of cerebral vessels, breakthrough of autoregulation, and blood–brain barrier (BBB) disruption.12–15 In fact, the neurologic symptoms of eclampsia are often interpreted as a form of hypertensive encephalopathy.8,16–18It is well known that pregnancy is associated with significant cardiovascular adaptation of both local and systemic circulations.2,19–22 Although the vascular changes that occur during pregnancy have been the subject of intense study in many organs, the effect of pregnancy and hypertension during pregnancy on the cerebral circulation is just coming to be understood. This review focuses on structural and functional changes in the cerebral circulation during normal pregnancy and the postpartum state that may contribute to the development of eclampsia, including changes in CBF autoregulation and cerebrovascular resistance (CVR) that enhance BBB permeability and hydrostatic brain edema. In addition, how hypertension during pregnancy, being somewhere between acute and chronic hypertension, affects the cerebral circulation is discussed.Eclampsia as a Form of Posterior Reversible Encephalopathy SyndromeEclampsia is defined in the obstetric literature as the new onset of seizures in a woman with preeclampsia, whereas preeclampsia is defined as blood pressure >140/90 mm Hg with significant proteinuria.1 Although it is seizure that defines eclampsia, some neurologic symptoms can precede the onset of seizure, such as persistent headaches, blurred vision, photophobia, and altered mental status.1,2,6 There has been considerable debate as to whether the neurologic symptoms of eclampsia arise from "overautoregulation" that causes vasospasm and ischemia or from hyperperfusion that causes cerebral edema formation.23 This uncertainty over the cause of eclampsia is likely because clinical findings of eclampsia have shown varying degrees of hemorrhage, cerebral edema, and vasculopathy.1,8,11 However, the reversibility of clinical neurologic signs and neuroradiologic lesions within a few days or weeks postpartum in most cases argues against the existence of true cerebral ischemic necrosis. In fact, the clinical and neuroimaging findings are more consistent with edema.5,8,13–15 For example, the neuroradiologic hallmarks of eclampsia are reversible abnormalities that appear on computed tomography and T2-weighted magnetic resonance and diffusion-weighted images with high apparent diffusion coefficient, all suggestive of edema.5,14,15,18,24–28The primary explanation for the pathogenesis of neurologic symptoms and edema formation during eclampsia is that it represents a form of reversible posterior leukoencephalopathy syndrome29 or posterior reversible encephalopathy syndrome (PRES).30 This syndrome is a variant of hypertensive encephalopathy with diverse causes, including immunosuppressive therapy, systemic lupus erythematosus, acute glomerulonephritis, and pregnancy.31 Both hypertensive encephalopathy and PRES can arise from an acute elevation in blood pressure that overcomes the myogenic vasoconstriction of cerebral arteries and arterioles causing loss of autoregulatory capacity, BBB disruption, and vasogenic edema.8,12–15 The concept that eclampsia can cause PRES has arisen from numerous similarities in clinical presentation including comparable imaging findings on computed tomography and MRI,3,5,18,31–33 the same neurologic symptoms (headache, vomiting, cortical blindness, and seizures),3,9,16,17 and the prompt reversibility of symptoms after blood pressure has been restored.3,9The difference between hypertensive encephalopathy and PRES is that PRES can develop without a significant elevation in blood pressure.31 In fact, eclampsia can occur at blood pressures that are considerably lower than those reported for hypertensive encephalopathy (discussed below),31,34 making the designation of PRES more appropriate. The occurrence of cerebral edema and neurologic complications at normal blood pressures during eclampsia suggests that autoregulatory breakthrough is not necessary but may be more related to diminished autoregulatory capacity or enhanced BBB permeability (because of either normal pregnancy or endothelial damage, discussed below) or a combination of both. In any case, the cerebral circulation is the primary effector of these symptoms and is central to the pathogenesis of eclampsia. Understanding how pregnancy and the postpartum state affect the structure and function of this unique vascular bed may provide important clues as to how eclampsia develops and to potential treatments of this devastating condition.Brain Edema in Pregnancy and EclampsiaBrain edema can be characterized as cytotoxic or vasogenic depending on whether or not the BBB is disrupted.34 Cytotoxic edema occurs when brain cells, most notably astrocytes, swell at the expense of the extracellular space while the BBB remains intact. Vasogenic edema occurs when cerebrovascular permeability is increased because of BBB disruption that allows an influx of plasma constituents into the brain and expansion of the extracellular space. Because the increase in brain water associated with vasogenic edema occurs within the closed space of the skull, edema causes progressive brain compression and the classic neurologic symptoms of headache, nausea, vomiting, cortical blindness, and convulsions.10,35 The edematous brain can also displace brain structures and reduce perfusion, ultimately leading to infarction or herniation, common causes of death in eclampsia.5,36,37 Although hypertensive encephalopathy-related brain edema occurs in several conditions including acute hypertension and cyclosporin A immunosuppressive therapy, it is most often reported in obstetrics cases.38,39The formation of vasogenic brain edema in hypertensive encephalopathy is caused by increased BBB permeability and/or enhanced water flux into the brain because of pathologically increased blood hydrostatic pressure.39–42 The cerebral endothelium that forms the BBB is unique in that in the intact brain, there is very low hydraulic conductivity and essentially no ionic or solute flux.43,44 This unique configuration makes the effect of hydrostatic pressure on capillary filtration minimal and is a protective influence against vasogenic brain edema. However, under conditions in which there is diminished autoregulation, an acute rise in blood pressure can severely increase hydrostatic pressure on the microcirculation, causing endothelial cell damage, increased BBB permeability, and vasogenic edema.41 This type of vasogenic edema is termed "hydrostatic brain edema" and is the primary explanation underlying the neurologic complications of hypertensive encephalopathy and eclampsia.40–42The term "hydrostatic brain edema" was introduced by Ishii et al40 in 1983 and results from an unfavorable hydrostatic pressure gradient between the cerebral blood vessels and brain tissue. Numerous studies in brain have shown that hydrostatic pressure alone is capable of causing BBB opening and edema formation.41,42,45,46 In fact, the hydrostatic pressure gradient seems to be the major factor in determining both the degree of the initial insult and the subsequent deterioration after the hypertensive event.42,45,46 Similarly, it is the change in hydrostatic pressure during eclampsia, when autoregulation is diminished, that likely contributes to vasogenic edema and the neurologic complications associated with this condition.42Our own study using a model of hypertensive encephalopathy in nonpregnant and late-pregnant rats found that whereas pregnancy did not affect the pressure at which autoregulatory breakthrough occurred, only late-gestation animals developed significant edema formation in response to autoregulatory breakthrough (Figure 1).47 These results suggest that pregnancy alone predisposes the brain to the neurologic complications of eclampsia by promoting hydrostatic brain edema when blood pressure is acutely elevated. It should be noted that this study was conducted during normal rodent pregnancy and suggests that an acute elevation in pressure has a greater effect on brain edema during late gestation than the nonpregnant state. While interesting, the mechanism by which pregnancy enhances cerebral edema in response to acute hypertension is not clear. In addition, it is also not clear how a preexisting disease, such as preeclampsia, which has been shown to produce endothelial dysfunction and oxidative stress,1 affects cerebral edema formation. Download figureDownload PowerPointFigure 1. A, CBF autoregulatory curves from nonpregnant (NP) and late-pregnant (LP) anesthetized rats determined using laser Doppler and acute phenylephrine infusion. Notice that autoregulation was intact in both groups of animals from ≈110 to 180 mm Hg as demonstrated by little change in CBF with pressure. However, at pressures above ≈180 mm Hg, breakthrough occurred, substantially increasing CBF. There was no difference in the pressure of breakthrough between NP and LP animals. B, Cerebral edema formation in response to autoregulatory breakthrough in the same NP and LP rats shown in A. Notice that only the LP animals developed edema formation at this time point (10 minutes) after breakthrough. *P<0.05 vs NP; ↑=P 120 mm Hg diastolic) was recorded in only 70 of 383 or 20% of subjects. In fact, 21% had normal blood pressure (ie, <140/90 mm Hg). Importantly, of 201 women whose blood pressures were recorded within 60 minutes of their first seizure, the mean diastolic pressure was only 97 mm Hg.80 The fact that some women with eclampsia do not have the clinical definition of hypertension has led to the suggestion that eclampsia is not always a progression from severe preeclamptic disease to seizure (eclampsia).81 This concept is also important for understanding the underlying cause of the neurologic complications of the disease. It is possible that the change in blood pressure necessary to promote hyperperfusion and hydrostatic brain edema is considerably lower in pregnancy, making an increase to normal pressures pathologic. Alternatively, the autoregulatory curve could be shifted to the lower range of pressure during pregnancy, possibly because of the lower blood pressures that occur over the course of gestation; however, our own studies in a rat model of pregnancy did not confirm this.47 Importantly, pressure alone may not be the only causative factor. Endothelial dysfunction that is known to occur in preeclampsia likely affects the cerebral endothelium as well, although how the BBB is affected under these conditions is not known.Several studies have attempted to measure CBF autoregulation during normal pregnancy, preeclampsia, and eclampsia.82–84 One study in which TCD was used to measure changes in CBF velocity in response to increases in blood pressure induced by a postural change from the left lateral to the supine position found that preeclamptic women had a more pronounced decrease in mean flow velocity, suggesting a stronger autoregulatory response.82 Measurement of dynamic CBF autoregulation, a noninvasive technique that uses physiological changes in MAP to assess autoregulation, was performed on patients with eclampsia and found a substantial disturbance in CBF autoregulation.83,84 This finding is not surprising given the strict similarities in the pathologic findings of eclampsia with hypertensive encephalopathy or PRES, including loss of autoregulation, hyperperfusion, and BBB disruption.Myogenic Activity and Endothelial Function During Normal Pregnancy and PostpartumAlthough clinical studies have provided valuable information regarding the nature of eclampsia, mechanistic studies are understandably difficult. We have used isolated and pressurized posterior cerebral arteries during normal pregnancy and the postpartum state to investigate how these gestational states affect the underlying cellular mechanisms of diameter regulation, including myogenic activity, endothelial vasodilator production, and smooth muscle reactivity.85 We found that arteries from both late-pregnant and postpartum animals underwent forced dilatation at considerably lower pressures than arteries from nonpregnant animals, suggesting that the autoregulatory curve is shifted to the lower range of pressures. This interpretation should be taken with caution, because this finding reflects only 1 isolated artery when in fact CBF autoregulation is influenced by several factors including neuronal, endothelial, and metabolic components, in addition to myogenic.86Pregnancy and the postpartum state also appear to affect endothelial vasodilator production and smooth muscle reactivity. Cerebral arteries from late-pregnant and postpartum animals constricted in a concentration-dependent manner to serotonin, whereas arteries from nonpregnant animals dilated.85 Because the dilation was in the presence of both cyclooxygenase and NO inhibition, these results suggest that arteries from nonpregnant animals produce endothelium-dependent hyperperpolarizing factor in response to serotonin that is not present in arteries during pregnancy or the postpartum state that are more dominated by NO. The significance of this change in vasodilator production by the cerebral endothelium is unclear; however, it is possible that these changes contribute to hemodynamic alterations during pregnancy, similar to the periphery.Perivascular InnervationCerebral pial vessels are innervated extrinsically (ie, ganglia are peripheral in origin) with fibers that contain neurotransmitters from sympathetic, parasympathetic, and trigeminal systems.87 Although these fibers are not thought to be important for control of basal CBF, sympathetic fibers are thought to limit hyperperfusion during acute elevations in pressure.76 Interestingly, it appears that pregnancy has a trophic effect on perivascular innervation of cerebral pial vessels (Figure 3). Aukes et al88 used a panneuronal stain to show that perivascular innervation of posterior cerebral arteries was increased during pregnancy in the Dahl salt-sensitive rat. Because specific neurotransmitters were not quantified, it is not clear what consequence, if any, this finding might have. Studies that investigate changes in specific neurotransmitters during pregnancy would be important to understanding the significance of these perivascular nerves. For example, trigeminal nerve fibers are nociceptive and may promote headache,89 the most common symptom of eclampsia,90 whereas sympathetic fibers have been shown to affect cerebral artery remodeling in response to chronic hypertension.91Download figureDownload PowerPointFigure 3. Photomicrographs of perivascular nerves surrounding posterior cerebral arteries from nonpregnant (NP) and late-pregnant (LP) rats. There was considerably greater staining of protein gene product 9.5, a pan neuronal stain, in arteries from LP vs NP animals. A, Photomicrograph of a cerebral artery from a LP normotensive rat. B, Photomicrograph of a cerebral artery from a NP hypertensive rat. C, Graph of perivascular innervation of posterior cerebral arteries from NP and LP rats demonstrating a hypertrophic effect of pregnancy on perivascular innervation (used with permission from Am J Physiol. 2007;292:H1071–H1076).88Cerebrovascular Remodeling During Hypertension in PregnancyChronic hypertension is associated with cerebrovascular remodeling that is thought to be protective of the brain.92,93 In particular, pressure-induced medial hypertrophy of both large and small cerebral arteries increases the wall:lumen ratio and serves to normalize circumferential wall stress that is elevated because of increased blood pressure.92–96 Both hypertrophy and remodeling of large and small cerebral arteries attenuate the increased pressure in downstream microvessels, thereby protecting the BBB from disruption.97 It should be noted that hypertension during pregnancy is a unique form of hypertension that is somewhere between acute and chronic. Therefore, the effect of hypertension during pregnancy on structural remodeling is largely unknown compared with what is known to occur during chronic hypertension.Although medial hypertrophy of cerebral arteries is considered protective of the BBB, pregnancy appears to prevent this response to hypertension, potentially increasing the susceptibility to edema formation. Our own study examined how hypertension during pregnancy, induced by NO synthase inhibition, affected medial hypertrophy of posterior cerebral arteries.98 NO synthase inhibition for just 7 days significantly raised arterial pressure in both nonpregnant and late-pregnant rats and caused significant medial hypertrophy in posterior cerebral arteries from nonpregnant animals. In contrast, cerebral arteries from late-pregnant animals lacked this response to hypertension and did not undergo medial hypertrophy. The observation that pregnancy prevents hypertensive remodeling and medial hypertrophy was further confirmed using another model of hypertension during pregnancy. A study that used Dahl salt-sensitive rats made hypertensive by feeding a high-salt diet for the last half of pregnancy (2 weeks) also found that only the nonpregnant rats (treated for the same time period) underwent remodeling, that is, the pregnant animals lacked any structural response to hypertension.88The mechanism by which pregnancy prevents hypertensive remodeling of cerebral arteries is not known but appears to be related to the pregnant state. Furthermore, the consequence of pregnancy preventing hypertensive remodeling of cerebral arteries is not clear but may promote forced dilatation at lower pressures and limit the rightward shift in the autoregulatory curve that would normally occur in response to this duration of hypertension. In addition, it is not known whether preexisting hypertensive remodeling can be reversed by pregnancy. Any reversal of hypertension-induced remodeling may further predispose women with chronic hypertension to eclampsia, because MAP is elevated, but without an increased wall: lumen ratio that is thought to be protective. The effect of pregnancy on hypertensive remodeling and medial hypertrophy of cerebral arteries is interesting and highlights an underlying mechanism by which pregnancy influences cerebrovascular structure in ways that can influence cerebral hemodynamics.BBB During Pregnancy and EclampsiaUnderstanding how pregnancy affects water flux in the brain is of p
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