Cerebrovascular Hemodynamics in Women

Abstract

Sex and gender, as biological and social factors, significantly influence health outcomes. Among the biological factors, sex differences in vascular physiology may be one specific mechanism contributing to the observed differences in clinical presentation, response to treatment, and clinical outcomes in several vascular disorders. This review focuses on the cerebrovascular bed and summarizes the existing literature on sex differences in cerebrovascular hemodynamics to highlight the knowledge deficit that exists in this domain. The available evidence is used to generate mechanistically plausible and testable hypotheses to underscore the unmet need in understanding sex-specific mechanisms as targets for more effective therapeutic and preventive strategies.

Increasing evidence from epidemiological and experimental studies highlight the importance of sex and gender in vascular health and disease. Differences based on sex and gender span clinical manifestations, pathophysiology, responses to treatment, and outcomes in all vascular beds, but more specifically brain, heart, and kidney. Men have a higher prevalence of coronary heart disease and stroke, with higher mortality rates than women until mid to late life, around the time of menopause, when this association is reversed.^1-3 Similarly, while aging is associated with increasing risk of stroke and coronary heart disease, the rate of increase for both conditions is much higher in older women.^2,4 Moreover, while age-adjusted mortality for cardiovascular disease has been declining, the extent of this decline has been less in women, and stroke-related outcomes remain consistently worse in women, except in the case of aneurysmal subarachnoid hemorrhage (SAH) where women seem to have more favorable outcomes.^4,5 On the other hand, despite a higher prevalence of chronic kidney disease in women, women with chronic kidney disease seem to have a better cardiovascular prognosis than men, even though women are less likely to start dialysis.^6-8

Age variable gender disparities in the incidence of and clinical outcomes from vascular disease among women have been largely ascribed to the actions of the sex steroid hormone 17β-estradiol (E2) and its receptors, estrogen receptor α (ERα) and β (ERβ), on the vascular endothelium.^9,10 The underlying mechanisms are complex. In addition to effects on endothelial function, estrogens influence blood pressure (BP) regulation, platelet function, and autonomic nervous system regulation. This review will focus on the vessels of the brain, but we will draw on research on other vascular beds where cerebrovascular data are lacking.

The cerebrovascular bed is regulated through myogenic, endothelial, autonomic, and metabolic mechanisms. These regulatory mechanisms, which maintain brain perfusion and meet the metabolic demands of neurons, are termed cerebral autoregulation, vasoreactivity (VR), and neurovascular coupling (NVC).^2,11-16 This review will summarize existing evidence that highlights possible hormonal and cellular pathways affecting regulatory mechanisms in the cerebrovascular bed and contributing to gender differences in cerebral hemodynamics and cerebrovascular disease. An appreciation of hemodynamic pathophysiplogy is particularly important to our understanding of sex-specific responses to stroke and to our understanding of the cerebrovascular complications of preeclampsia–eclampsia. To contribute to this field and to promote the generation of testable hypotheses and the identification of potential therapeutic targets, this review will also describe noninvasive methods for assessing cerebrovascular hemodynamics in humans.

Autoregulation

Definition

Cerebral autoregulation refers to the regulatory mechanisms which serve to maintain relatively constant blood flow to the brain by rapidly adjusting cerebrovascular resistance while compensating for fluctuations in cerebral perfusion pressure (CPP).^17-19 Cerebrovascular resistance is primarily governed by arteriolar diameter, although larger vessels may also contribute. CPP, in turn, reflects the pressure difference between cerebral arterial and venous beds. However, since an accurate measure of cerebral venous pressure is not readily available, the intracranial pressure (ICP) is used as a surrogate, and CPP is commonly calculated as the difference between the mean arterial pressure (MAP) and ICP. Cerebral autoregulation is mediated by myogenic, metabolic, and neurogenic mechanisms.^20,21 Given the high metabolic demand of brain tissue and the need for a constant supply of oxygen and glucose, any condition that impairs cerebral autoregulation will allow harmful changes in CPP to be transmitted to the neurovascular bed. Stroke, head trauma, SAH, severe hypertension, or space-occupying brain lesions may all result in impairments in cerebral autoregulation.²²

A variety of methods have been used to assess the integrity of cerebral autoregulation. Early investigations of autoregulation were limited to the steady-state behavior of cerebral blood flow (CBF). Using this approach, steady-state blood flow changes were measured in response to steady-state changes in the BP. However, the time-consuming and invasive nature of these procedures^23,24 and the need to manipulate BP using vasoactive medications are impractical for testing autoregulation in acute cerebrovascular disorders. In addition to this practical limitation, since cerebrovascular resistance is constantly changing, optimizing CBF through fast-acting dynamic processes, the traditional steady-state approaches, lack the temporal resolution necessary for assessment of this dynamic process.

The introduction of transcranial Doppler ultrasound (TCD) to measure CBF velocity²⁵ provided a powerful tool for noninvasive assessment of dynamic CBF responses to various stimuli, including changes in MAP.^16,17 TCD, which can provide continuous beat-to-beat measurement of the CBF velocity in the basal cerebral arteries with high temporal resolution, has become the most commonly used tool to study CBF regulation in humans. Dynamic cerebral autoregulation (dCA) is assessed by measuring transient changes in the CBF velocity in response to sudden rapid changes in MAP. Sudden changes in MAP can be induced using a variety of techniques such as the rapid defl ation of bilateral thighcuffs,¹⁸ hand grip,²⁶ valsalva maneuver,²⁷ transient hyperemic response test,^28,29 and the sit-to-stand method.^30,31 The blood flow responses are then characterized and quantified by several different derived variables and reported as specific measures of autoregulation.¹¹

As an alternative to measuring responses to induced changes in MAP, spontaneous oscillations in arterial BP ranging from 0.02 to 0.4 Hz that occur in humans without external BP manipulations can be measured and compared with associated variations in CBF velocity to achieve a measure of dCA.^32-37 This approach, which is the most physiological and noninvasive method for assessing the integrity of cerebral autoregulation at the bedside, is the one most frequently used in patients with acute cerebrovascular injuries.

Transfer function analysis can be used to quantify the transfer of the BP oscillations to CBF velocity as a measure of autoregulation. The extent to which BP oscillations are reflected in CBF velocity oscillations is expressed using three parameters, gain, phase shift, and coherence. Given that diameter changes of the cerebral arterioles in response to pressure changes are not fast enough to block high-frequency (>0.2 Hz) oscillations in BP, fast oscillations are passed along and cerebral autoregulation is not engaged in the high frequency ranges. However, slower oscillations (0.03–0.2 Hz) can be offset by autoregulation working through diameter changes in cerebral arterioles. In these low or autoregulatory frequency ranges, gain reflects the magnitude, and phase shift reflects the time delay of the transmitted BP oscillation to CBF velocity oscillation. Higher phase shift and lower gain are reflective of more efficient autoregulation.^38-41 Coherence is a measure of the relation between cerebral blood flow velocity (CBFV) and BP oscillations across different frequencies; in other words, it can be used to estimate the extent to which these oscillations approximate one another.

Influence of Sex

The influence of sex on systemic and cerebral hemodynamics has been the focus of many publications; however, small sample sizes and methodological differences have hindered a better understanding of the mechanisms underlying some of the observed differences. Clinically, orthostatic hypotension as well as other hypotensive disorders of BP regulation are much more common in women than men.⁴² BP starts to rise in the 3rd decade of life in men, but not until 4th or 5th decade in women, corresponding to timing of menopause. By the age of 70, more women have hypertension than men, and the incidence of hypertension continues to rise in women.⁴³ Additionally, while markers of whole body sympathetic activity and vascular resistance are tightly correlated in men across the adult life span, this is not the case for young women. In other words, the vasoconstrictive effect of the sympathetic nervous system is dampened in young women, possibly as a result of concurrent β2-adrenergic vasodilation that offsets α-adrenergic vasoconstriction. In older women like men, however, a clear relationship emerges between markers of whole body sympathetic activity and vascular resistance. There is evidence to suggest that the loss of estrogen may contribute to an increase in sympathetic activity and loss of β-adrenergically mediated endothelial vasodilatation.⁴⁴

Spectral analysis of beat-to-beat heart rate (HR) and arterial pressure variability has been increasingly utilized to study the dynamic interaction of the sympathetic and parasympathetic control of cardiovascular autonomic regulation.⁴⁵ Studies using this approach have demonstrated that across the adult life span, compared with men, women have lower resting HRs, lower R-R intervals, and diastolic BP (DBP) variability in the low frequency ranges, as well as lower MAP and CBF velocity variability in the very low frequency range at rest and during sit-to-stand maneuvers.⁴⁶ While attributing neurophysiological correlates to the low- and high-frequency spectral components of HR and BP have been controversial, it has been argued that an increase in sympathetic activity may be associated with the enhancement of low-frequency and the attenuation of the high-frequency oscillations.^47,48 Applying the same spectral analysis to BP and CBF velocity oscillations to assess cerebral autoregulation (transfer function analysis) across adult life span, women demonstrate lower gain and coherence at rest and a higher phase shift during sit–stand maneuvers than men, suggesting a better dCA for women in both conditions.^46,49 At the same time, woman seem to have lower baroreflex sensitivity than men.⁴⁶

The integrative physiological model that emerges from these studies is complex. These studies show that aging is associated with increased sympathetic activity in both genders, but more pronounced in women as evidenced by increasing incidence of hypertension and lower baroreceptor sensitivity and lower HR, BP, and CBF variability. Yet, throughout life women continue to manifest more efficient dCA parameters. One possible explanation for this observation is that the cerebrovascular bed may also be more vasoconstricted as a result of increased sympathetic tone in women.^49-51 This suggestion is based on work demonstrating improved dCA during hypocapnia, which increases cerebrovascular resistance (higher vasoconstricted state).¹⁸ Sex hormone levels don’t seem to provide an explanation, since dCA remains unchanged throughout the menstrual cycle in premenopausal women,⁴⁰ and hormone replacement therapy (HRT) in postmenopausal women does not seem to impact dCA.³⁴ Interestingly, studies using phase contrast magnetic resonance imaging (MRI) show that women have higher CBF than men across the adult age range.⁵² The higher CBF was observed despite a smaller total brain tissue volume, suggesting that there may be a higher cerebral metabolic rate in women than men.⁵³ So, while women may have better autoregulatory mechanisms, their age-related susceptibility to cerebrovascular injury may be related to loss of systemic regulatory mechanisms which exposes the higher metabolic demands of the female neurovascular unit to greater vascular injury despite better autoregulation. Given that XX neurons seem to be more susceptible to proapoptotic cell death, whereas XY cells seem to be more vulnerable to excitotoxic cell death,⁵⁴ there may indeed be sex-dependence to ischemic tolerance, neuronal injury, and recovery.

Pregnancy and Preeclampsia–Eclampsia

The cerebrovascular system undergoes adaptive changes to maintain stable cerebral perfusion during pregnancy, while other organs, such as the uterus, heart, and kidney, undergo substantial increases in perfusion and filtration.⁵⁵ Major hemodynamic changes associated with pregnancy work to maintain a stable CBF and BP despite cardiac output increases of up to 50% to sustain a hypervolemic state in the setting of augmented circulatory demand.^56,57 Maternal plasma volume and cardiac output increases reach a maximum at 20 weeks of gestation, accompanied by a decline in peripheral vascular resistance. Cerebral adaptation to this increased inflow occurs through an increase in resistance in the MCA. Although this adaptation maintains relatively stable CBF during pregnancy, in the postpartum period when there is a normal fall in the CPP, it is associated with a period of decreased CBF.⁵⁸ Changes in carbon dioxide (CO₂), perivascular innervation, hormones, cytokines, and other circulating factors are thought to be responsible for these adaptive alterations.⁵⁹

Although the overall number of strokes in women in reproductive age is low, pregnancy and the postpartum period confer an increased stroke risk, resulting from altered coagulation and vascular hemodynamics.⁶⁰ Preeclampsia and eclampsia account for much of this increased stroke risk. These hypertensive disorders of pregnancy have been associated with altered cerebrovascular hemodynamics and impaired autoregulation, and these physiologic impairments are believed to be a major source of the clinical consequences of the hypertensive cerebral vasculopathy of pregnancy.⁶¹ In normal pregnancy, autoregulatory index (ARI, that is, the change in the cerebrovascular resistance per second in response to a change in arterial BP) is in the high normal range, suggesting that the normal pregnant state demands more efficient cerebrovascular regulation.^62,63 The enhanced autoregulatory capacity of normal pregnancy has been attributed to the relative hypocapnia seen in pregnancy⁶⁴ (vasoconstricted cerebrovascular bed); however, observed ARI differences persist after adjusting for end-tidal CO₂. In preeclampsia–eclampsia, cerebral arterioles undergo changes that impede their autoregulatory capacity (dilation and constriction abilities) to manage pulsatile changes in arterial pressure, leading to hyperperfusion as well as hypoperfusion injuries resulting from autoregulatory failure.⁶² CBF studies in preeclampsia have mainly used TCD to assess hemodynamic changes. Compared with normal pregnancy, CPP is significantly higher in preeclampsia, while dCA is normal.^62,65 Only one small study has shown dCA to be less efficient in pregnant women with chronic hypertension and preeclampsia compared with normal and gestational hypertension pregnancies where ARI was also in the low normal range.⁶⁶ It appears that in most cases of preeclampsia dCA remains adequate, but when dCA becomes inefficient, perfusion injury, edema formation, and neurological complications of hypertensive encephalopathy, seizures, and strokes ensue.⁶⁷ In patients with chronic hypertension, the cerebrovascular system remodels to shift the autoregulatory curve to tolerate higher pressures.⁶⁸ It is speculated that this vascular remodeling does not occur during pregnancy, rendering the cerebrovascular bed vulnerable to the acute perfusion injury, for example, in the setting of hypertension leading to posterior reversible encephalopathy syndrome (PRES).⁶⁹ The observed alterations in the expression of angiogenic factors and resulting systemic endothelial dysfunction may also involve the cerebrovascular endothelium, where dysfunction could also play a role in the progression to cerebral edema and, hence, from preeclampsia to eclampsia.⁷⁰

Stroke

Gender disparities in stroke incidence are age-dependent. Until the age of 45, women have a lower age-adjusted incidence of ischemic stroke and a better prognosis for neurological recovery.^71,72 Between 45 and 54 years of age, coincident with the onset of menopause, the incidence of stroke begins to increase. During this period, there is also a surge in obesity and metabolic syndrome that contributes to increased stroke risk.⁷³ Between the ages of 55 and 85, the incidence of stroke is comparable between men and women. After 85 years of age, women are at highest risk of ischemic stroke.⁷² Furthermore, recurrence rates and poststroke motor disability are significantly higher in older women,^54,74 as is stroke-related mortality.^75,76

Gender-specific risk factors for ischemic stroke in young women include oral contraceptives containing estrogens, migraine with aura, and rare causes such as fibromuscular dysplasia, antiphospholipid antibody syndrome, and Takayasu arteritis.^5,77,78 During pregnancy (hemorrhagic), and especially postpartum (both ischemic and hemorrhagic), the risk of stroke increases with a significant contribution from preeclampsia–eclampsia. Mechanisms underlying gender disparities in stroke risk and outcome after menopause are unclear. Studies of cerebral autoregulation in acute ischemic stroke have produced conflicting results and have not shown any gender-specific differences. Studies in lacunar and large-vessel stroke in the first 72 to 96 hours have demonstrated impaired dCA^26,79,80 in both stroke types. Low phase shift dCA has been the parameter consistently altered in ischemic stroke, contrary to gain which does not seem to have an association.^81,82 In these studies, this difference was independent of severity of stroke, BP, sex, and age, lasting for at least 1 to 2 weeks.⁸³ In another study of minor stroke, dCA was preserved in the acute phase, but in the subacute phase, ARI was decreased with a trend for lower phase shift, representing mild autoregulatory disruption.⁸² More recently, it was demonstrated that the efficacy of dCA during the first 6 hours after stroke symptom onset was associated with smaller infarct lesion size at 24 hours and a better functional outcome at 3 months.⁸⁴ Autonomic dysfunction after stroke, a known phenomenon, was suggested as a possible mechanism for dCA impairment.²⁶ Similarly, patients with migraine have been shown to have less efficient autoregulation compared with healthy controls.^85,86 Given the link between early dCA impairment and neurological outcome, it is possible that some of the gender differences in clinical outcome may stem from early dCA differences. If indeed women demand a more efficient autoregulatory system than men, or if their cerebrovascular beds are accustomed to higher autoregulatory efficiency, even mild decreases in the effectiveness of autoregulation could pose a greater risk of neurovascular injury for them. Further studies are needed to advance our understanding of sex differences that might contribute to the better stroke outcomes in women, comparable to those observed in men.

Similar to ischemic stroke, sex-specific differences have also been observed in hemorrhagic strokes [primary intracerebral hemorrhage (ICH), aneurysmal SAH, and hemorrhagic transformation of ischemic stroke]. Epidemiologic studies in ICH have demonstrated sex differences in hematoma location.⁸⁷ There is a reported female predilection for cerebellar and right hemispheric hematoma formation.⁸⁸ Women may have an overall lower ICH incidence.⁸⁹ BP response to treatment, cerebral edema, and development of deep venous thrombosis (DVT) also show sex differences.⁹⁰ Treatment response shows some gender disparity as well, with an inverse association between rate of MAP decline and mortality only observed in men, but not in women.⁹⁰ Finally, in a prospective study of ICH, female sex was the only independent predictor for DVT.⁹¹ Mechanisms underlying these observed differences are not completely understood. Studies so far have demonstrated that loss of female sex hormones (as in menopause) influence outcome after brain injury,⁹² and in a prospective observational study, postmenopausal women seemed to have a significantly higher risk for ICH.⁹³ SAH represents 5% of all stroke causes,⁹⁴ and female sex is a risk factor for aneurysm formation, mainly in the postmenopausal period;⁹⁵ however, females seem to have better clinical outcomes. Although no gender differences have been explored, autoregulation can be impaired in the first days after SAH,^96,97 and those with less effective autoregulation after SAH seem to have a higher risk of delayed cerebral ischemia (DCI).⁹⁸ The hemodynamic autoregulatory profile of patients who developed DCI was that of lower gain and lower autoregulatory slope, suggesting a smaller capacity to increase flow with pressure augmentation.⁹⁸ While autoregulatory changes have not been observed in animal models of SAH, female animals tend to have less volume of subarachnoid blood, lower rise in ICP, less vascular and brain injury, and lower 24-hour mortality compared with males.⁹⁹ Males seem to have a greater ICP rise and larger vascular and inflammatory responses than females.¹⁰⁰

Similar to primary cerebral hemorrhage, in acute ischemic stroke patients with hemorrhagic transformation, where cerebral microvascular injury and less effective autoregulation may represent a biologic pathway between white matter injury and hemorrhagic transformation,¹⁰¹ early impairment in dCA (low phase shift) during the acute stroke phase has also been associated with delayed hemorrhagic transformation.¹⁰² Given the existing gender differences in clinical outcomes and risks associated with these stroke subtypes, it would be worthwhile to explore whether sex differences in autoregulatory efficiency may be possible mediators or modifiers for observed gender differences in risk and clinical outcome.

Vasoreactivity

Definition

A healthy cerebrovascular bed is inherently reactive to changes in the partial pressure of arterial CO₂ (PaCO₂).¹⁰³ Hypercapnia results in vasodilation of cerebral arterioles and consequent increase in CBF, while hypocapnia results in vasoconstriction and decrease in CBF.^104,105 This interaction between PaCO₂ and CBF, termed cerebral VR, is regulated at the level of arterioles and precapillary sphincters¹⁰⁶ by mechanisms that are mediated at the level of K⁺ channels in the smooth vascular muscle¹⁰⁷ as well as the vascular endothelium through nitric oxide (NO)-mediated pathways.¹⁰⁸ CBF responses to step changes in CO₂ in humans start within 30 seconds of inhalation and reach a peak within 6 seconds after onset.¹⁰⁹ TCD has been used extensively to study cerebral VR and has established clinical utility in stroke risk assessment in several cerebrovascular pathologies, such as carotid stenosis, intracranial atherosclerosis, SAH, and moyamoya disease.^110,111 Cerebral VR protocols tend to vary based on the stimulus or challenge used and the analytical approach for assessing the CBF and CO₂ relationship. Some use an inhaled gas mixture of 8% CO₂ with 21% O₂ (hypercapnia with normoxia), while others use 5% CO₂ with 95% O₂ (hypercapnia with hyperoxia). Hypocapnia is achieved by hyperventilation in most protocols. Others use breath-holding as a hypercapnic stimulus. Acetazolamide can also lead to a mild extracellular acidosis and hence intracranial vasodilation, and is an alternative to inhaled gasses or breath-holding as a vasodilatory stimulus.¹¹² TCD is the noninvasive tool with the best temporal resolution most often used in clinical and experimental settings. Across most selected experimental studies, normal “global” CBF reactivity to changes in PaCO₂ is ~3.8%/mm Hg within the PaCO₂ range of 35 to 55 mm Hg—higher in the hypercapnic than hypocapnic range. Arterial spin labeling (ASL) MRI, which can provide much greater spatial resolution than TCD, has been utilized more recently to measure the reactivity of cerebral small vessels within the cortical gray matter.¹¹³ While VR has been studied in healthy aging and chronic cerebrovascular injures, for practical reasons, these studies have been limited in the acute phase of neurovascular injuries.

Influence of Sex

The relationship between cerebral VR and female sex remains unclear, and contradictory results have been reported. While some studies have shown lower VR in young women, particularly in those younger than 65 years of age,^49,114 and in postmenopausal women younger than 65 years of age, others have reported higher VR in younger women,^115-117 and some have reported no gender differences.¹¹⁸ A possible explanation for the observed controversies reported by different groups may be a consequence of different methodologies used for VR protocols. BP changes during CO₂ inhalation and the interindividual variability of the breath-holding duration are unmeasured confounders in many of these studies. Definitive conclusions warrant studies with larger sample sizes and tighter protocol adherence. The impact of hormones on cerebral VR is also controversial. While menopause has not been shown to alter VR significantly,¹¹⁹ VR has been shown to be significantly altered over the course of the menstrual cycle and the changes have been positively correlated with ovarian hormone concentrations.¹²⁰ However, reports of the impact of HRT on cerebral VR have been conflicting, with one showing no benefit,¹²¹ while another showed improved reactivity and reduced coronary heart disease and mortality when started early after menopause.¹²² The hormonal state of women in many of these studies has been heterogeneous with significant variability in the menstrual phase for premenopausal women, the hormonal state of perimenopausal women, and time postmenopause in older women.¹²³

Hypertensive disorders of pregnancy seem to impact cerebral VR as well. Cerebral VR seems to be significantly reduced in preeclampsia–eclampsia when compared with normotensive pregnancies.^124,125 This finding is consistent with a state of vasoconstriction in the hypertensive disorders of pregnancy that is unresponsive to vasodilatory stimuli such as hypercapnia.

Unlike dCA, cerebral VR has been more challenging to study in patients with acute stroke and hemorrhage, and as a result there are no studies examining gender differences in cerebral VR in acute neurovascular injuries. The few studies that have examined cerebral VR in acute cerebrovascular injuries, such as acute ischemic stroke and SAH, seem to show that VR is impaired early in these conditions.^126-129 Animal studies also support these findings and show that while NVC is not altered in the first few hours after SAH, cerebral VR is completely lost.¹³⁰

Given that cerebral VR is a measure of endothelial function in the cerebrovascular bed, and therefore, NO-mediated, it is expected that this measure should be regulated by estrogen and the hormonal state of female patients. This hypothesis is supported by studies of peripheral endothelial function using flow-mediated dilation (FMD). This is a well-established technique that allows researchers to examine endothelial function and assess cardiovascular risk noninvasively, even during pregnancy.¹³¹ Studies have shown that FMD decreases with increasing age in both genders, up to 70years for men and 80 for women (p < 0.001). However, age-related decline in FMD was steepest after age 45 for women, while in men, a steady decline was observed after age 30.¹³² Also, in women who developed preeclampsia as compared with normal pregnancies, FMD was also lower before the clinical diagnosis of preeclampsia (2029 weeks gestation), at the time of preeclampsia, and for 3 years postpartum.¹³³ Steeper age-related decline in endothelial function may be one mechanism for worse stroke-related outcomes in older women, in whom plasticity may be hampered by lower VR to increased metabolic demand. There is clearly an unmet need for more studies of sex-specific changes in cerebral VR in acute neurovascular injuries.

Neurovascular Coupling

Definition

NVC, or functional hyperemia, defines the close relationship between CBF and neuronal activity regulated at the level of the neurovascular unit.^134,135 Astrocytes and GABAergic interneurons connect with cortex-penetrating arterioles, and intramural propagation of vascular signals, mediated by excitatory and inhibitory neurons, produces remote vasodilation of upstream pial arterioles.¹³⁶ NVC can be exemplified by visual activation of the occipital cortex, which elicits an immediate and robust increase in CBF velocity in the posterior cerebral artery (PCA).¹³⁷ Cognitive testing during TCD monitoring of the anterior cerebral circulation has also been used in several studies to demonstrate increased CBF velocity in response to motor and cognitive tasks.^138-140 Functional MRI (fMRI), position emission tomography (PET), and TCD can all be used to assess NVC. While TCD can noninvasively measure the hyperemic response, PET and fMRI mainly measure the metabolic activity of the neurovascular unit. Aging, vascular disease, and neurodegenerative pathologies can all impair NVC. Similar to VR, assessment of the NVC in the acute state of neurovascular injuries has been limited, and most studies have focused on cognitive disorders of aging.

Influence of Sex

Impact of sex on NVC has not been specifically addressed in previous studies. However, given the central role NO plays in regulating neurovascular responses, it is very likely that hormonal changes, especially, estrogen, have a strong influence across the adult life span with prominent sex differences.¹²⁹ For example, a few studies have6 assessed NVC during normal pregnancy and hypertensive disorders of pregnancy. A recent history of preeclampsia has been shown to dampen NVC in the posterior circulation during visual activation.¹⁴¹ Also, at 24 to 28 weeks of gestation, women with impaired utero-placental vasoregulation seemed to have enhanced NVC during visual stimulation, but this response was not necessarily predictive or protective of eclampsia.¹⁴² Several mechanisms may account for this dysregulation, but enhanced placental NO bioavailability may be a critical factor.¹⁴³ fMRI studies have also shown gender differences in blood oxygen level-dependent (BOLD) amplitudes during neural responses to flickering stimuli, where despite a higher visual evoked potential (VEP) amplitude, the BOLD amplitude is significantly lower in women.¹⁴⁴ While the mechanisms underlying this observation have not been identified, differences in baseline hemodynamics as well as structural differences (i.e., more gray matter in women versus more white matter in men) have been suggested.¹⁴⁵

Stroke, aging, and traumatic brain injury all seem to impair NVC, but the impact of sex has not been specifically examined in all these conditions. Cognitive impairment and dementia seem to be more frequent in women, which may be related to a higher number of elderly women than men, particularly over 80 years of age.¹⁴⁶ However, at a comparable stage of Alzheimer’s disease (AD), women seem to have more prominent cognitive deficits than men.¹⁴⁷ Increasing evidence links cerebral hypoperfusion and neurodegeneration to AD and vascular dementia, and assessment of cerebrovascular hemodynamics may be an important tool in early identification of at-risk individuals.^148,149 Given gender disparities in stroke and cognitive impairment and the established link between age-related differences in cognitive performance and NVC,¹⁵⁰ a better understanding of the impact of gender on NVC could provide new targets and approaches to enhance motor recovery after stroke or to prevent cognitive decline in women. Also, in animal models of SAH, while CO₂ is impaired before NVC, impairment of NVC can occur secondarily and further aggravate SAH-induced cerebral ischemia and subsequent brain damage.¹²⁹ Recent studies demonstrate that targeting NVC is pharmacologically possible and can lead to improved cognitive function,¹⁵¹ particularly in postmenopausal women.¹⁵² These findings hold promise for novel therapeutic targets in acute and chronic neurovascular injuries.

Summary

Women have a longer life expectancy with a hormonal profile that significantly varies across their life span, in particular, during their reproductive years. The impact of sex as a biological variable in vascular risk and neurovascular response to injury seems to not only depend on the hormonal milieu, but also on age-related changes in physiological response to the hormonal milieu. Estrogens clearly play a protective role in vascular function, but the benefits of estrogens seem to be linked to other age-related cellular and systemic changes that occur across the female life span and are time variable. In the cerebrovascular bed which can be assessed through measures of autoregulation, VR, and NVC, it appears that healthy women have better dCA and higher resting CBF. Systemically, young premenopausal women also seem to have lower sympathetic tone and a better overall BP profile, resulting in less systemic endothelial injury. Premenopausal young females are also better protected against vascular injury as a result of the higher number of endothelial progenitor cells and greater proangiogenic potential that is also regulated by E2 concentrations.¹⁵³ Overall, it seems that the female vascular system is better protected and operates at a higher efficiency in the childbearing years, possibly a biological result of the enhanced hemodynamic demand of the pregnant state. Therefore, neurological sequelae of hypertensive disorders of pregnancy can ensue when dCA and VR become less effective, even below the level of frank impairment.

While we know that impaired dCA and cerebral VR are associated with worse clinical outcomes in ischemic and hemorrhagic strokes, whether sex differences in these measures also account for gender-specific outcomes in these conditions remains unknown. Similarly, age-related cognitive decline and dementia seem to be linked to NVC, but whether aging and vascular risk factors have a sex-specific impact on NVC is unknown. Clearly, there is a significant knowledge deficit that hinders our ability to prevent and treat a devastating condition in women. This review is intended to generate testable hypotheses that can lead to more effective sex-specific preventive strategies and therapeutic targets in vascular disease. Now that bedside assessment of the cerebrovascular bed can be noninvasively and repeatedly achieved, we are poised to test some of these hypotheses and correct the existing knowledge deficit on sex-specific changes in cerebrovascular hemodynamics that could serve as the substrates for vascular health disparities that exist for women.