Deficiencies in estrogen-mediated regulation of cerebrovascular homeostasis may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in menopausal and postmenopausal women

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Summary

Despite the catastrophic consequence of ruptured intracranial aneurysms, very little is understood regarding their pathogenesis, and there are no reliable predictive markers for identifying at-risk individuals. Few studies have addressed the molecular pathological basis and mechanisms of intracranial aneurysm formation, growth, and rupture. The pathogenesis and rupture of cerebral aneurysms have been associated with inflammatory processes, and these have been implicated in the digestion and breakdown of vascular wall matrix. Epidemiological data indicate that the risk of cerebral aneurysm pathogenesis and rupture in women rises during and after menopause as compared to premenopausal women, and has been attributed to hormonal factors. Moreover, experimental evidence supports a role for estrogen in the modulation of each phase of the inflammatory response implicated in cerebral aneurysm pathogenesis and rupture. While the risk of aneurysm rupture in men also increases with age, this increased risk has been attributed to other recognized risk factors including cigarette smoking, use of alcohol, and history of hypertension, all of which are more common in men than women. We hypothesize, therefore, that decreases in both circulating estrogen levels and cerebrovascular estrogen receptor density may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in women during and after menopause. To test our hypothesis, experiments are needed to identify genes regulated by estrogen and to evaluate gene expression and intracellular mechanisms in cells/tissues exposed to varying concentrations and duration of treatment with estrogen, metabolites of estrogen, and selective estrogen receptor modulators (SERMs). Furthermore, it is not likely that the regulation of cerebrovascular homeostasis is due to the actions of estrogen alone, but rather the interplay of estrogen and other hormones and their associated receptor expression. The potential interactions of these hormones in the maintenance of normal cerebrovascular tone need to be elucidated. Additional studies are needed to define the role that estrogen and other sex hormones may play in the cerebrovascular circulation and the pathogenesis and rupture of cerebral aneurysms. Efforts directed at understanding the basic pathophysiological mechanisms of aneurysm pathogenesis and rupture promise to yield dividends that may have important therapeutic and clinical implications. The development of non-invasive tools such as molecular MRI for the detection of specific cells, molecular markers, and tissues may facilitate early diagnosis of initial pathophysiological changes that are undetectable by clinical examination or other diagnostic tools, and can also be used to evaluate the state of activity of cerebral aneurysm pathogenesis before, during, and after treatment.

Introduction

An intracranial aneurysm is a prevalent acquired cerebrovascular disease that can cause a catastrophic subarachnoid hemorrhage (SAH). The most frequently occurring aneurysms are saccular and considered to be the combined result of a multifactorial pathogenic complex. Both genetic and acquired factors have been investigated. Hemodynamic stress at arterial bifurcations and congenital medial defects are also believed to contribute to aneurysm development. Other factors, such as hypertension, smoking, atherosclerosis, and alcohol intake, are commonly related to the pathogenesis and eventual rupture of cerebral aneurysms.

A growing body of evidence indicates that the risk of cerebrovascular events in women rises after menopause [1], but the benefit of postmenopausal estrogen replacement therapy (ERT) for cerebrovascular disorders such as stroke is not clear. Some clinical studies do not support the benefit of ERT for cerebrovascular disease [2]. A number of clinical trials associated with the Women’s Health Initiative (WHI) have assessed the potential benefits of hormone replacement therapy (HRT) for protection against the development of cardiovascular disease and memory loss in menopausal women. For example, the results of the WHI Memory Study (WHIMS) suggest that HRT increases the risk of stroke and dementia in menopausal women. This finding has called into question the results of hundreds of basic science studies that have suggested that estrogen could protect brain cells from damage and improve cognition. For example, ERT in hypoestrogenic postmenopausal women has been shown to reduce the risk and severity of neurodegenerative decline associated with cerebrovascular disorders [3], [4].

Despite the catastrophic consequence of ruptured intracranial aneurysms, very little is understood regarding their pathogenesis, and there are no reliable predictive markers for identifying at-risk individuals. Few studies have addressed the molecular pathological basis and mechanisms of intracranial aneurysm formation, growth, and rupture. The formation, growth, and rupture of cerebral aneurysms have been associated with inflammatory processes, and these have been implicated in the digestion and breakdown of vascular wall matrix. Remodeling of the vascular extracellular matrix (ECM) has been found to be involved in the pathogenesis of vascular diseases like aortic aneurysm, atherosclerosis, and arteritis. The potential mechanisms by which estrogen protects against cerebrovascular events, however, is less understood. Currently, no current pathogenic hypothesis successfully reconciles the clinical, epidemiological, pathological, biochemical, and molecular features of the disease. As with other illnesses, efforts directed at understanding the basic pathophysiological mechanisms of aneurysm formation, growth, and rupture promise to yield dividends that may have important therapeutic and clinical implications. For example, if specific enzymes can be identified as responsible for proteolysis in cerebral aneurysms, then inhibition of these enzymes may prove effective in slowing or even preventing aneurysm expansion. Moreover, high field molecular MRI may be used to determine the physiological status of cerebral aneurysm growth in vivo by employing contrast agents that are sensitive to various inflammatory markers implicated in cerebral aneurysm pathophysiology. The development of non-invasive tools such as molecular MRI for the detection of specific cells, molecular markers, and tissues may facilitate early diagnosis of initial pathophysiological changes that are undetectable by clinical examination or other diagnostic tools, and can also be used to evaluate the state of activity of cerebral aneurysm pathogenesis and other cerebrovascular disease states before, during, and after treatment. These potential applications are of great interest in clinical practice.

In formulating the following hypothesis, we provide evidence implicating a protective role for estrogen in each phase of an inflammatory response associated with cerebral aneurysm pathogenesis and rupture.

Section snippets

Hypothesis

We hypothesize that decreases in both circulating estrogen levels and cerebrovascular estrogen receptor density may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in women during and after menopause. Our hypothesis regarding the pathophysiology of cerebral aneurysms is based on experimental studies of (1), the epidemiology of cerebral aneurysm formation, growth, and rupture (2), the role of inflammatory processes and disease in the pathophysiology of cerebral

Epidemiology of cerebral aneurysm formation, growth, and rupture

The main cause for spontaneous subarachnoid hemorrhage (SAH) is rupture of cerebral aneurysms [5]. The reported incidence of aneurysmal SAH ranges from 6 to 21 per 100,000 people per year [6]. Among those individuals who suffer from a ruptured cerebral aneurysm, 50% die at the time of rupture or shortly thereafter, and 25% suffer permanent disability, including paralysis, and loss of speech, vision, and motor coordination [7], [8]. The remaining 25% are at increased risk of stroke, recurrent

Discussion

The experimental evidence presented in this paper supports the hypothesis that deficiencies in estrogen may be responsible for the increased risk of cerebral aneurysm formation, growth, and rupture observed in menopausal and postmenopausal women. The distribution of ER-α and ER-β in different cerebrovascular cells and beds of origin with special regards to different biological actions is an emerging topic of interest. For example, radiolabeling studies have indicated that tissues not

Conclusion

We have proposed that a decline in circulating levels of estrogen, and a decrease in the density and expression of estrogen receptors in ECs and VSMCs of cerebral blood vessels may contribute to an increased risk of cerebral aneurysm pathogenesis and rupture in women during and after menopause. This hypothesis is supported by substantial experimental evidence implicating a modulatory role for estrogen in the regulation of cerebrovascular homeostasis. We have provided experimental evidence

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