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
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
References (236)
Estrogen replacement therapy and stroke
Prog Cardiovasc Dis
(1995)Genetics and aneurysm formation
Neurosurg Clin N Am
(1998)The pathobiology of aortic aneurysms
J Surg Res
(2004)Ascorbic acid enhances 17 beta-estradiol-mediated inhibition of oxidized low density lipoprotein formation
Atherosclerosis
(2000)The relation of oxidized LDL autoantibodies and long-term hormone replacement therapy to ultrasonographically assessed atherosclerotic plaque quantity and severity in postmenopausal women
Atherosclerosis
(2001)Estrogens inhibit copper and cell-mediated modification of low density lipoprotein
Atherosclerosis
(1991)- et al.
Estradiol-17beta as an antioxidant: some distinct features when compared with common fat-soluble antioxidants
J Lab Clin Med
(1996) 17Beta-estradiol inhibits oxidized low density lipoprotein-induced generation of reactive oxygen species in endothelial cells
Life Sci
(2001)- et al.
Effects of estrogen on susceptibility to oxidation of low-density and high-density lipoprotein in postmenopausal women
Maturitas
(1998) Vascular smooth muscle cells as target for estrogen
Biochem Biophys Res Commun
(1993)
Regulation of the lipopolysaccharide signal transduction pathway by 17beta-estradiol in macrophage cells
J Steroid Biochem Mol Biol
Down-modulation of interleukin-6 gene expression by 17 beta-estradiol in the absence of high affinity DNA binding by the estrogen receptor
J Biol Chem
Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys
J Am Coll Cardiol
Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene
J Biol Chem
The vascular endothelial system in the pathogenesis of inflammation and systemic rheumatic diseases: relation to the neuroendocrine system
Rheum Dis Clin North Am
Hypercholesterolemia promotes inflammation and microvascular dysfunction: role of nitric oxide and superoxide
Free Radic Biol Med
17Beta-estradiol inhibits apoptosis of endothelial cells
Biochem Biophys Res Commun
Akt plays a central role in the anti-apoptotic effect of estrogen in endothelial cells
Biochem Biophys Res Commun
Cardiovascular health and disease in women
N Engl J Med
A clinical trial of estrogen-replacement therapy after ischemic stroke
N Engl J Med
Estrogen replacement therapy in older women: a neuropsychological and brain MRI study
J Am Geriatr Soc
Incidence, aetiology, and prognosis of primary subarachnoid haemorrhage. A study based on 589 cases diagnosed in a defined urban population during a defined period
Acta Neurol Scand
Unruptured intracranial aneurysms: a review
J Neurosurg
Genetics of intracranial aneurysms
Neurosurgery
Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study
Stroke
The unchanging pattern of subarachnoid hemorrhage in a community
Neurology
Subarachnoid and intracerebral hemorrhage: natural history, prognosis, and precursive factors in the Framingham Study
Neurology
Intracranial arterial aneurysms in children and adolescents
J Neurosurg
Berry aneurysms of the circle of Willis; results of a planned autopsy study
Neurology
The long-term outcome in patients with multiple aneurysms. Incidence of late hemorrhage and implications for treatment of incidental aneurysms
J Neurosurg
The significance of unruptured intracranial saccular aneurysms
J Neurosurg
The natural history of unruptured intracranial aneurysms
N Engl J Med
The necropsy demonstration of cerebral aneurysms by intra-arterial injection
Proc Aust Assoc Neurol
Report on the cooperative study of intracranial aneurysms and subarachnoid hemorrhage. 3. Subarachnoid hemorrhage unrelated to intracranial aneurysm and A-V malformation. A study of associated diseases and prognosis
J Neurosurg
Familial cerebral aneurysms. A bias for women
Stroke
Incidence of multiple intracranial aneurysms. Influence of arterial hypertension and gender
J Neurosurg
Gender-related differences in aneurysmal subarachnoid hemorrhage
J Neurosurg
Age and outcome after aneurysmal subarachnoid hemorrhage: why do older patients fare worse?
J Neurosurg
Risk factors for subarachnoid hemorrhage
Stroke
Cigarette smoking, alcohol use, and subarachnoid hemorrhage
Stroke
Cigarette smoking as a risk factor for stroke. The Framingham Study
Jama
Stroke and alcohol consumption
N Engl J Med
Subarachnoid hemorrhage and hormonal factors in women. A population-based case-control study
Ann Intern Med
Direct evidence of hypertension and the possible role of post-menopause oestrogen deficiency in the pathogenesis of berry aneurysms
J Neurol
Biological imaging for the diagnosis of inflammatory conditions
BioDrugs
Are cerebral aneurysms atherosclerotic?
Stroke
Immunocytochemical studies of atherosclerotic lesions of cerebral berry aneurysms
J Neuropathol Exp Neurol
Clinicopathological features of non-atherosclerotic cerebral arterial trunk aneurysms
Neuropathology
Non-atherosclerotic fusiform cerebral aneurysms
Can J Neurol Sci
Genesis of cerebral aneurysms – an update
Acta Neurochir (Wien)
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