Impact of myocardial infarction on cerebral homeostasis: exploring the protective role of estrogen

Myocardial infarction pathophysiology

MI is characterized by cardiomyocyte death caused by an ischemic insult, typically due to thrombotic blockage of a coronary vessel following plaque rupture^[18]. This event arises from the destabilization or rupture of a susceptible atherosclerotic plaque, or endothelial erosion, which releases thrombogenic substances, activates platelets, and triggers the coagulation cascade, leading to thrombus formation. The thrombus obstructs coronary blood flow, causing ischemia and tissue necrosis, which is detectable by elevated cardiac biomarkers^[2,19]. The severity of infarction depends on the degree of occlusion, the extent of necrosis, and collateral circulation^[19].

This cardiac hypertrophy progresses when the heart fails to compensate for increased ventricular volume. Hence, numerous mechanisms are altered post-MI; these mechanisms include alterations in hemodynamics, the autonomic nervous system, baroreflex sensitivity, the RAAS, sarcoplasmic reticulum calcium handling, the beta-adrenergic pathway, and oxidative stress, which are observed in both human subjects and experimental models^[19].

In parallel to understanding the pathophysiology of MI, identifying modifiable and non-modifiable risk factors is essential for prevention. Controllable factors include hypertension, diabetes, high cholesterol, and smoking, while age, sex, and genetic predisposition remain unmodifiable^[20]. The Framingham study was pivotal in identifying key risk factors such as hypertension, diabetes, obesity, hyperlipidemia, smoking, and sedentary behavior, leading to significant reductions in CVD rates in developed countries^[21]. However, developing nations experienced a rise in CVD rates due to rapid economic transitions^[22]. The INTERHEART study involving a multiethnic cohort from 52 countries, included 15,152 first-time MI patients and 14,820 age- and sex-matched controls, further highlighted the substantial association between common risk factors (such as smoking, dyslipidemia, hypertension, diabetes, abdominal obesity, and psychosocial factors) and increased MI risk^[23].

At the cellular level, upon coronary occlusion, aerobic metabolism is halted, and metabolic byproducts accumulate. Ultrastructural changes in cardiomyocytes include depletion of glycogen, distortion of the transverse tubular system, and mitochondrial swelling. The heart survives the initial ischemic event, and a complex cascade of molecular, cellular, neurohumoral, hemodynamic, and morphological responses ensues^[24]. The heart's limited regenerative capacity leads to repair predominantly through inflammatory response and collagen scar formation, resulting in infarct expansion: thinning of the cardiac wall, and ventricular dilation^[25,26]. Functionally, the loss of cardiomyocyte leads to reduced ejection volume and increased ventricular wall stress, which triggers compensatory mechanisms such as hypertrophy^[27,28].

Systemic effects of MI and its impact on the brain

Beyond the heart, MI triggers a systemic inflammatory response that impacts distant organs, notably the brain. Systemic inflammation following MI exacerbates atherosclerotic inflammation and destabilizes plaques in arteries remote from the initial event^[29]. In parallel, MI heightens endoplasmic reticulum (ER) stress in the brain, characterized by increased levels of PERK, GRP78, and ATF4 proteins^[30]. This ER stress promotes protein aggregation in glial cells, reflecting the pathological features observed in neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease, and Amyotrophic Lateral Sclerosis^[30]. Notably, treatment with small-molecule ER stress relievers, attenuated these effects, underscoring the link between cardiovascular events and neurodegenerative changes^[30].

Homeostasis in the central nervous system (CNS) is maintained through a complex regulatory network, with astrocytes playing a key role in electrochemical processes such as ion regulation, neurotransmitter release, and signal transduction^[31].

The impact of MI on brain function is well-documented. A preclinical study by Kaplan et al. showed that acute MI is directly linked to brain function impairment. MI induces systemic inflammation and an elevated RAAS activation, which affect remote organs including the brain and have deteriorating implications for brain perfusion^[11]. Human studies also reveal an association between MI and cerebral infarction. A cross-sectional study of patients who underwent both brain and cardiac MRI found that MI was specifically linked to cortical cerebral infarction, with no association to general infarction. The burden or size of MI was also unrelated to infarction risk, except in cases of apical MI, which showed a distinct correlation with cortical infarction^[32].

Impact of heart dysfunction on CBF regulation

Heart failure, a common sequela of MI, greatly increases brain vulnerability. Although the brain accounts for only 2% of body weight, it receives roughly 12% of cardiac output (CO)^[33]. HF-related reductions in CO impair cerebral blood flow (CBF) even when systemic blood pressure appears maintained^[33,34]. CBF is regulated by several robust mechanisms, including cerebral autoregulation, neurovascular coupling, and cerebrovascular reactivity to carbon dioxide and oxygen^[33]. Moreover, several other regulatory mechanisms ensure the tight control of CBF, including the mean arterial pressure, cerebral metabolism rate, and perivascular nerve activity. Any disruption in these regulatory mechanisms can lead to disturbances in CBF^[35]. While cerebral autoregulation usually keeps CBF constant within its blood pressure range, both acute and chronic changes in CO can still alter CBF even when blood pressure is unchanged^[33]. Reduced CO in heart failure impacts cerebral autoregulation, decreasing CBF. Although brain arterioles dilate to compensate for lower output, this adaptive response has limits, impairing cerebral autoregulation and cerebrovascular reactivity to CO₂.

Notably, the neurohumoral system, activated in congestive heart failure (CHF), further induces vasoconstriction in both peripheral and cerebral vessels. Over time, cerebral resistant vessels adapt chronically to low CO, which blunts autoregulation and further reduces CBF. Consequently, CHF patients face a higher risk of critically low CBF, even during routine activities^[34]. Research has connected older individuals with heart failure and global cognitive impairment to cerebral hypoperfusion, reduced blood flow velocity in the middle cerebral arteries (MCA-BFV), and elevated levels of inflammatory markers such as TNF-α, c-reactive protein (CRP), IL-6, IL-1, and toll-like receptor 4. Hypoperfusion also drives glial activation, mitochondrial dysfunction, loss of dendritic spines (leading to synaptic dysfunction), and neuronal apoptosis^[8,36]. Elevated CRP levels, in particular, correlate with impaired memory, slower information processing speed, and reduced executive function^[37].

Oxidative stress is another critical factor contributing to cognitive deficits. The brain's high metabolic rate, oxygen consumption, and lipid-rich content make it vulnerable to oxidative damage and lipid peroxidation^[38]. Elderly individuals with memory deficits exhibit elevated lipid peroxidation, while Alzheimer's patients show poor cognitive function linked to weakened antioxidant defenses. Similarly, heart failure is marked by high lipid peroxide levels, increased inflammation, and reduced antioxidant biomarkers like coenzyme Q10^[39].

MRI studies reveal structural brain changes in heart failure patients, including reduced gray matter density in cognitive regions (e.g., precuneus, cingulate cortex, hippocampus); correlating with lower ejection fractions and higher NT-pro-BNP levels^[40]. Kaplan et al. demonstrated that, despite an increased proportion of blood flow directed to the brain, total brain perfusion remains reduced for at least 30 days post-MI, illustrating the sustained cerebral impact^[11].

Impact of MI on neurons and cognition

Following acute MI, the inflammatory response significantly impacts neuronal function and recovery. Microglia, the central nervous system's immune cells, produce cytokines upon activation, leading to neuroinflammation, a process increasingly linked to the risk of neurodegenerative disorders. A study by Thackeray et al. using coronary artery ligation on mice and PET imaging of the mitochondrial translocator protein (TSPO), a marker of activated microglia, revealed elevation of activated microglia at 1 week post-MI, which declined at 4 weeks but reappeared with progressive heart failure. Similar findings were observed in patients where elevated cardiac TSPO signals post-MI were accompanied by neuroinflammation^[41]. In addition to that, it was revealed that MI induces neuronal microtubule damage, increasing miR-1 levels and decreasing TPPP/p25 protein expression in the hippocampus of adult male C57BL/6 mice and Sprague Dawley (SD) rats^[42]. In rats, a significant increase of 40% to 50% in the proportion of activated microglia in the hypothalamic paraventricular nucleus (PVN) between 4 and 16 weeks post-MI was demonstrated. However, no significant increase in activated microglia was observed 24 h or 1 week after MI. It was suggested that microglial activation in the PVN does not occur immediately following MI but becomes evident over time and persists. Consequently, activated microglia play a role in the sustained elevation of cytokine levels observed after MI^[43].

Beyond inflammation, MI triggers oxidative and pathological changes in the brain. In MI model using wild-type and AD-prone APP/PS1 mice, MI-treated mice exhibited poorer performance in the social recognition test, Morris water maze, and plus-maze discriminative avoidance task. These behavioral changes were accompanied by elevated reactive oxygen species (ROS) levels and increased amyloid-β (Aβ) peptide aggregates and tau protein phosphorylation in the mouse brain, pathological features of AD. Additionally, microglia in MI-treated mice shifted to a more proinflammatory phenotype^[44]. Another rat study conducted 48 h post-MI, it showed a significant increase in activated and dystrophic microglia in the prefrontal cortex, hippocampus, thalamus, and PVN, alongside hypertrophic astrocytes. Dystrophic microglia, linked to tau pathology and early neurodegeneration, were suggested to contribute to neuronal dysfunction and cognitive decline^[45]. MI, followed by 72 h of reperfusion, revealed apoptosis in the amygdala, hippocampus, and vermis. MI rats showed significantly reduced PI3K activity, an increased Bax/Bcl-2 ratio, heightened caspase-3 activity, and a rise in TUNEL-positive cells in the amygdala, indicating localized apoptosis in the limbic system three days post-MI^[46].

Another study explored brain and heart protein changes after MI with a data-independent acquisition mode proteomics approach and found that microglial activation in the brain cortex was observed as early as 1 day post-MI in rats, remaining elevated at 3 and 7 days post-MI. This early activation suggests direct brain involvement following cardiac injury and helps explain the increased risk of stroke, depression, and cognitive impairment in MI and heart failure patients. Moreover, two brain-specific differentially expressed proteins were highlighted: ELOVL5, which supports myelin structure and nerve conduction, was altered, possibly contributing to neurological symptoms post-MI, and ABCG4, involved in lipid homeostasis and amyloid-β transport, was upregulated in the brain cortex, linking MI-induced neuroinflammation with Alzheimer's-like pathology^[47].

Although clinical data are more limited, emerging evidence reflects these preclinical observations. In a pilot study on 48 post-MI patients, 81.3% showed transient increases in serum S100B levels, a marker of glial alterations, with depressive symptoms^[48]. Knowing that heart failure manifests after MI, it was reported that heart failure mediates low CO and CBF reduction^[11]. For instance, worsening cognition in heart failure with reduced ejection fraction was primarily associated with a reduction in CBF, with a strong association seen in older adults^[49]. Building on that, in a study involving Stage C heart failure patients, lower hippocampal CBF was associated with higher depression scores and memory impairments^[50]. Moreover, midlife abnormalities in cardiac structure and diastolic function were associated with lower cognitive performance, consistent with findings from the Multi-Ethnic Study of Atherosclerosis and the Framingham Offspring Study. Interestingly, left ventricular hypertrophy and increased atrial volume, but not decreased ejection fraction, were associated with impaired cognition, possibly through impaired brain perfusion or micro-embolisms^[51]. MRI studies further revealed significant right hippocampal atrophy and left frontal cortical atrophy in heart failure patients, particularly in regions regulating depression and executive function^[32,49,52].

Recent large-scale, longitudinal studies have confirmed the association between MI and cognitive outcomes. In a Danish National Registry study of over 300,000 MI survivors, MI was associated with an increased risk of vascular dementia (adjusted hazard ratio [aHR] 1.35), with a significantly higher risk observed in those who had a stroke after the MI (aHR 4.48). However, MI was not associated with an increased risk of AD, suggesting a vascular-specific cognitive pathway^[53]. Similarly, in a pooled analysis of six US cohorts (n = 30,465 adults), those who had suffered a MI (n = 1,033) did not experience acute cognitive decline, but did show accelerated deterioration in memory and executive function over time^[54]. In another study, 37% of patients hospitalized for MI had cognitive dysfunction, with 25% retaining deficits six months later. Notably, new cases of cognitive dysfunction also emerged during follow-up, often associated with depressive symptoms and sleep disturbances^[55].

Another study conducted on a biracial cohort of middle-aged adults found that premature CVD is significantly associated with worse cognitive performance, accelerated cognitive decline, and structural brain changes in midlife. These effects were observed across various cognitive domains and were not entirely explained by shared risk factors such as stroke, demographics, or cardiovascular risk factors. Importantly, the presence of white matter hyperintensities and altered white matter integrity in those with premature CVD parallels brain changes typically seen in the elderly^[56].

These findings reinforce the role of systemic inflammation, oxidative stress, and cerebrovascular dysregulation observed in animal models. Furthermore, elevated markers such as S100B and altered CBF in post-MI suggest early glial injury and neurovascular impairment^[48,50]. These data indicate that post-infarction follow-up should go beyond cardiac function to include cognitive screening, particularly in older adults or those with multiple cardiovascular risk factors [Table 1].

Impact of MI on the blood-brain barrier

Physiological processes regulating CBF include perivascular nerve constriction, arterial dilation, astrocyte end-foot modifications of arterial diameter, and endothelial release of hemodynamic and vasoactive elements. The BBB separates the brain from the peripheral circulation, and is composed of cerebral microvascular endothelial cells, astrocytes, pericytes, neurons, and extracellular matrix, which are particularly vulnerable to aging pathophysiology and neurological damage^[16]. The concept of “cardiogenic dementia”, initially proposed in The Lancet, highlights cognitive decline in patients following heart disease. Cognitive impairment is prevalent among individuals with heart failure, with up to 50% exhibiting varying degrees of cognitive decline^[57]. In healthy older adults, cognitive decline tends to occur at a very gradual pace, often becoming noticeable only over decades. However, older adults who develop heart failure are likely to experience a more rapid deterioration in cognitive function^[58]. Additionally, it is understood that coronary heart disease and atherosclerosis contribute to inflammation, impacting both large and small blood vessels in the brain. For instance, hypertension can compromise the cerebrovascular endothelium, raising BBB permeability. This increased permeability allows potentially damaging substances to infiltrate brain tissue, leading to neuroinflammation, particularly in white matter. Moreover, vascular risk factors can, through neuroimmune pathways and oxidative stress, stimulate the production of Aβ, which itself can cause vasoconstriction. Remarkably, reduced CBF and abnormal hemodynamic responses to neural activity are also observed in AD^[59].

As heart failure remains the leading cause of hospitalization in the U.S.^[60], its detrimental effects on the brain are a significant concern. Factors such as advanced age, multimorbidity (presence of multiple chronic conditions), and shared risk factors contribute to altered brain function and the potential development of cognitive impairment^[58]. Importantly, the early stages of heart failure induce vascular cognitive impairment due to impairment of BBB permeability. A study employing Tgαq*44 (model of progressing heart failure) and control FVB (wild‐type control) mice, using the novel object recognition (NOR) test, demonstrated that Tgαq44 mice exhibit cognitive impairment. Additionally, these mice showed notable activation of astrocytes (GFAP) and glial cells (IBA-1), indicating neuroinflammatory processes^[61].

Recent findings highlight the role of inflammatory mediators in BBB disruption and neuroinflammation following MI. Elevated levels of IL-17A are observed in circulation and the brain during heart failure after MI. These increased levels contribute to both neuroinflammation and sympathetic activation. IL-17A disrupts BBB integrity, as demonstrated in vitro and in vivo models, by increasing transcytosis and degrading tight junction proteins. In a study involving male SD rats subjected to coronary artery ligation to induce heart failure, some heart failure rats received bilateral PVN microinjections of interleukin 17 receptor A small interfering RNA or a scrambled small interfering RNA adeno‐associated virus. Expression analysis revealed augmented caveolin‐1, a transcytosis marker, and reduced tight junction proteins in heart failure rats. Treatment with interleukin 17 receptor A small interfering RNA significantly attenuated BBB permeability in the PVN and reversed the expression of caveolin-1 and tight junction-associated proteins. These results suggest that enhanced IL-17A/IL-17 receptor A signaling promotes BBB permeability in heart failure by increasing caveolar transcytosis and degrading tight junctions^[62].

Additionally, MI triggers specific molecular and cellular mechanisms that intensify cognitive decline. Following MI, there is an accumulation of advanced glycation end products (AGEs), particularly Nε-(carboxymethyl)lysine (CML), in the vasculature of the heart^[63]. CML buildup is intensified by inflammation and oxidative stress, further contributing to inflammation and ROS production. Moreover, studies in atherosclerotic mice show CML accumulation in cerebral microvasculature, which is associated with cerebrovascular disease and cognitive decline. Post-MI, elevated levels of CML and NADPH oxidase 2 (NOX2) have been detected in the cerebral microvasculature, peaking between 6 h and 5 days after MI onset, likely driven by systemic inflammation. Reduced CBF and increased circulating CML levels post-MI further exacerbate cerebral inflammation and oxidative stress. The heightened presence of CML and NOX2 may indicate dysfunction in the brain, contributing to MI-associated depression and dementia^[64] [Figure 1].

Figure 1. Pathophysiological pathways linking myocardial infarction to cognitive decline. This diagram illustrates the mechanisms by which cardiovascular dysfunction contributes to cognitive impairment. Reduced cardiac function, indicated by decreased EF and CO, triggers systemic inflammation, which causes the release of cytokines and the activation of perivascular macrophages through angiotensin II signaling. This cascade disrupts CBF, promoting the production of ROS, Aβ aggregation, and tissue injury, which exacerbates neuroinflammation. Neuroinflammation activates microglia and astrocytes, further leading to the release of proinflammatory cytokines. These processes compromise the integrity of the BBB, facilitating the progression of cognitive impairment. EF: Ejection fraction; CO: cardiac output; CBF: cerebral blood flow; ROS: reactive oxygen species; Aβ: amyloid beta; BBB: blood-brain barrier. Created in BioRender. Zouein, F. (2025), Available from: https://BioRender.com/e58z159.

Types of MI and clinical perspectives

MI is classified into type 1 and type 2. Type 1 MI results from atherothrombotic CAD, typically triggered by plaque rupture or erosion. Diagnostic criteria include a rise and/or fall in cardiac troponin (cTn) levels, ischemic symptoms, ECG changes, and evidence of a new coronary thrombus^[65].

In contrast, Type 2 MI, on the other hand, occurs when there is a mismatch between myocardial oxygen supply and demand without acute atherothrombotic plaque disruption. It can be triggered by acute stressors such as gastrointestinal bleeding or sustained tachyarrhythmia, and its diagnosis also involves a rise in cTn levels with evidence of oxygen supply-demand imbalance^[66].

Sex difference in MI: diagnosis, risk factors and cardiovascular burden in women with a focus on MI and menopausal transition

Accurate diagnosis of MI necessitates an evaluation of all clinical information, with coronary angiography serving as a crucial tool in distinguishing between different MI subtypes, particularly type 1 MI^[67]. Studies show that Type 1 MI tends to occur in younger individuals, with higher cardiac troponin T and CK-MB levels compared to Type 2 MI, which is more common in older women with comorbidities such as heart failure, kidney disease, and atrial fibrillation^[68-70]. Women generally experience their first MI 6 to 10 years later than men, largely due to the protective cardiovascular effects of estrogen, which modulates lipid profiles and body fat distribution^[71]. Estrogen promotes a less atherogenic lipid profile partly by binding to ApoB-100, influencing LDL metabolism and contributing to lower LDL cholesterol levels^[72].

However, the risk factors for MI differ markedly between sexes. Hypertension, smoking, and diabetes confer a disproportionately higher excess risk of MI in women than in men^[73]. For instance, smoking substantially increases the risk of ST-segment elevation myocardial infarction (STEMI) in women, particularly younger women^[74]. Moreover, perimenopausal and postmenopausal women exhibit higher LDL cholesterol levels and greater systemic inflammation compared to men, exacerbating their susceptibility to MI^[75,76].

A study included a non-CHD cohort (individuals without prior coronary heart disease); younger women exhibited a markedly lower risk of developing CHD and MI compared to men of the same age, highlighting a strong female advantage in early adulthood. However, this protective effect diminished progressively with increasing age, as the sex-related hazard ratios for CHD and MI rose, indicating a narrowing gap between men and women in older age groups. In contrast, in the post-MI cohort, sex differences in outcomes were minimal, and age did not significantly modify the association between sex and the risk of CHD or MI. One notable exception was heart failure, where older women post-MI had slightly worse outcomes compared to their male counterparts^[77].

The menopausal transition represents a “critical window” for increased cardiovascular risk. Premature menopause (before age 40) significantly elevates the risk of cardiovascular diseases, including MI, compared to menopause at the typical age^[78]. This period is associated with unfavorable changes in body composition, lipid profiles, and vascular function^[79]. Post menopause, the decline in estrogen levels leads to further deterioration in lipid metabolism and vascular health, with studies showing that postmenopausal women exhibit elevated levels of proatherogenic factors such as proprotein convertase subtilisin/kexin type 9 (PCSK9), which is associated with increased risk of coronary artery disease (CAD) and major adverse cardiovascular events^[80,81].

Estrogen and estrogen receptors

Burgeoning evidence shows that E2, the most biologically active form of estrogen, has extensive effects on neurological, cognitive, neurodevelopmental, and neurodegenerative processes, as well as various behaviors and physiological functions in both males and females. 17β-estradiol exerts wide-ranging effects on the brain via estrogen receptors (ERs), including ERα, ERβ, and G-protein coupled estrogen receptor (GPER1), influencing cognitive function, neuroprotection, and aging. It was believed that circulating estrogens mediate their effects primarily through ERα and ERβ, which, upon activation, function as homodimers or heterodimers to regulate gene transcription through the estrogen-response element. In addition to genomic actions, estrogens also activate rapid, non-genomic signaling pathways, particularly those involving cytosolic ERs.

ERα and ERβ are ubiquitously distributed in the brain, where they coordinate neuroprotective signaling cascades and modulate CBF, energy metabolism, inflammation, and oxidative processes^[82-84]. The phosphoinositide 3-kinase (PI3K)/Akt pathway plays a key role in the rapid, membrane-initiated actions of ERα. A study examined E2 effects on PI3K/Akt signaling in the hypothalamic arcuate nucleus (ARC) and ventrolateral ventromedial nucleus (vlVMN), both involved in energy homeostasis. In the ARC, E2 did not significantly activate the PI3K/Akt pathway, as phosphorylated Akt (pAkt) levels were unchanged across wild-type (Erα^+/+), ERα knockout (Erα^-/-), and nonclassical ERα signaling (Erα^-/AA) mice. Estrogen's influence on energy balance in the ARC is independent of the PI3K/Akt pathway. In contrast, E2 significantly activated the PI3K/Akt pathway in the vlVMN, with marked pAkt induction in Erα^+/+ mice. This effect was absent in Erα^-/- mice but restored in Erα^-/AA mice, indicating that nonclassical ERα signaling is sufficient for Akt activation in the vlVMN. Thus, the vlVMN mediates estrogen’s regulation of energy homeostasis via PI3K/Akt, while the ARC relies on different mechanisms. Estrogen treatment, beyond PI3K/Akt signaling, also normalized energy expenditure, improved glucose and insulin sensitivity, and reduced serum leptin concentrations, highlighting its critical role in preventing obesity and metabolic syndrome through nonclassical ERα pathways^[85].

Estrogens play a crucial role in body-weight regulation, evidenced by the weight gain seen in postmenopausal women and ovariectomized (OVX) female rodents, which can be mitigated by estrogen supplementation. The anti-obesity effects of estrogens are primarily mediated by ERα in specific brain regions. Additionally, estrogens enhance hippocampal learning and memory through rapid activation of signaling cascades, including PI3K, protein kinase A, protein kinase C, phospholipase C, and mitogen-activated protein kinase. These pathways modulate synaptic transmission, protein phosphorylation, and dendritic spine density^[82]. More supporting data came from a study by Phan et al. that showed administering 17β-estradiol or an estrogen receptor-α agonist (but not an ER-β agonist) into the dorsal hippocampus significantly improved discrimination learning in female mice. This was accompanied by increased dendritic spine density in CA1 neurons. Notably, the estrogen-induced spinogenesis reduced CA1 α-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptor activity, likely due to receptor internalization, creating silent or immature synapses^[86]. 17β-estradiol and ERα agonists enhance social recognition, object recognition, and object placement performance, particularly following systemic administration or hippocampal infusion. ERβ activation primarily improves spatial learning. Both 17β-estradiol, ERα agonists, and GPER agonists increase dendritic spine density in the CA1 hippocampus. Evidence showed that systemic GPER activation also enhances social and object recognition, though its role in object placement learning remains unclear^[87].

Both the estrous cycle and sex influence the number and types of neuronal and glial profiles containing classical ERs, as well as synaptic levels in the rodent dorsal hippocampus. A recent study explored the role of the membrane estrogen receptor GPER1 in synaptic plasticity within the dorsal hippocampus of mice^[88]. GPER1 immunoreactivity (IR) was most prominent in the pyramidal cell layer and interneurons of the dentate gyrus, with the highest density in the stratum lucidum of CA3. GPER1-IR was also observed in unmyelinated axons and glial profiles, with estrogen increasing axonal labeling in females. The GPER agonist G1 replicated some estradiol-induced changes, such as increased postsynaptic density protein (PSD95)-IR in the strata oriens, lucidum, and radiatum of CA3, though only estradiol increased Akt phosphorylation. GPER1 modulates synaptic plasticity through distinct molecular pathways^[88]. In terms of ER distribution within the CNS, ERβ proteins were found to be abundantly expressed in the granulosa cells of the ovary, epithelial cells of the prostate, and in cell populations within the anteroventral periventricular nucleus (AVPV) and paraventricular hypothalamic nucleus in rats^[89]. Interestingly, in vivo investigations indicated that combining immunoreactivity for ERβ with that for ERα encompassed all regions in the mouse CNS, where binding was detected via autoradiography^[90]. ERα is broadly distributed at low levels in the rodent brain, with the highest expression in the hypothalamus, hippocampus, and cortex^[91], while high Esr2 (which encodes Erβ) expression was detected in the hippocampus^[92], anteroventral periventricular nucleus (AVPV), bed nucleus of stria terminalis, hypothalamic PVN, supraoptic nucleus, and medial amygdala and more than half of kisspeptin neurons in female AVPV expressed Esr2^[93].

Further evidence from normal midlife women participants at varying hormonal stages during menopause revealed neurological symptoms such as changes in thermoregulation, mood, sleep, and cognition. Despite the importance of ERs in neural function, knowledge about their activity in the human brain is limited. Using 18F-fluoroestradiol PET imaging, a study showed that ER density increases with the menopause stage, indicating higher ER density postmenopause. ER density was lowest in premenopausal women, with intermediate levels in perimenopause, particularly in brain regions such as the pituitary, amygdala, and hippocampus. E2 acts as a “master regulator” of neurological function through ERs such as ERα, ERβ, and GPER1, influencing synaptic plasticity, neurogenesis, and gene expression. Higher ER density may be compensatory for declining estrogen levels and was associated with poorer memory and predicted mood and cognitive symptoms in postmenopausal women^[83] [Table 2].

Influence of estrogen on the heart

ERs play roles beyond their endocrine functions, modulating the cardiovascular, renal, and immune systems through their anti-inflammatory and anti-apoptotic pathways. They help prevent necrosis of cardiomyocytes and endothelial cells and reduce cardiac hypertrophy^[94]. E2 protects against cardiac dysfunction, enhances nitric oxide synthesis, and limits vascular cell proliferation, providing protective benefits regardless of gender. These effects are mediated by ERs (ERα, ERβ, or GPER), through genomic or non-genomic pathways, which help maintain cardiovascular function and prevent tissue remodeling^[94,95].

Involvement of E2 in cardio-protection was demonstrated in both male and female rodents. A study investigated cardiomyocyte-specific overexpression of ERα (ERα-OE) in transgenic mice following MI, revealed significant changes in left ventricle (LV) morphology 2 weeks post-MI: increased LV volume and decreased wall thickness were observed in wild-type mice and male ERα-OE mice, but not in female ERα-OE mice. ERα-OE enhanced the expression of angiogenesis (VEGF) and lymphangiogenesis (Lyve-1) markers, promoting neovascularization in the peri-infarct area in both sexes. Notably, female ERα-OE mice exhibited reduced fibrosis, and greater JNK phosphorylation post-MI compared to males^[96].

Further mechanistic insights were gained from studies using ERα knockout (ERKO) mice, which showed reduced nitric oxide (NO) production and increased oxidative stress, suggesting that ERα helps maintain NO levels and prevents NOS-3 downregulation. During reperfusion, ERKO hearts show greater calcium accumulation, mainly in the mitochondria, leading to ATP depletion, mitochondrial dysfunction, oxidative stress, and myocardial structural damage, including contraction bands and mitochondrial destruction^[97].

The role of ERβ has also been clarified in a heart failure model induced by pressure overload. A preclinical experimental study demonstrated that ERβ activation using diarylpropionitrile (DPN) improved heart function in male mice with severe heart failure. DPN treatment increased EF, reduced fibrosis, and promoted angiogenesis, while normalizing collagen I and TGF-β1 expression. In contrast, treatment with an ERα agonist had no significant effect on EF, fibrosis or angiogenesis. In vitro, DPN restored the expression of fibrotic markers to control levels^[98].

To examine the impact of long-term estrogen deprivation, ovariectomized (ACOV) models were used in heart failure induced by aortic constriction (AC) in female guinea pigs. ACOV animals showed worsened cardiac function, impaired Na⁺ extrusion, and reduced Na⁺/K⁺ ATPase current density, leading to calcium dysregulation and diastolic dysfunction. Supplementation with 17β-estradiol (ACOV + E) restored global and cellular cardiac function to levels similar to those of intact controls. Estrogen improved the amplitude and decay rates of Ca²⁺ transients and shortened the duration of the action potential at 90% repolarization (APD₉₀), also reducing ventricular hypertrophy depending on the pathological insult^[99]. Complementary findings in Wistar rats further demonstrated the time-sensitive effects of E2 post-ischemia. Hearts subjected to 30 min of regional ischemia showed improved function when treated with pacing postconditioning (PPC) or short-term E2 administration during reperfusion. However, long-term E2 treatment for six weeks abolished the protective effects of PPC. PPC increased brain natriuretic peptide expression, reduced TNF-α levels in cardiomyocytes and coronary effluent, and decreased infarct size while enhancing contractility and coronary dynamics^[100] [Table 3].

Overall, these findings indicate that estrogen exerts robust cardioprotective effects in experimental models of heart failure, as ovariectomy exacerbates cardiac dysfunction, while estrogen supplementation reverses these effects by improving both cellular and global cardiac function. These protective actions appear to be mediated in a phase-specific manner, with ERα contributing to early benefits during acute MI and reperfusion via vascular support and mitochondrial preservation, and ERβ playing a more prominent role in later stages by reducing fibrosis, modulating neuroinflammation, and enhancing cognitive recovery. Strategically targeting these receptor subtypes based on the pathological phase may enable more tailored and effective neuroprotective interventions.

Influence of estrogen deficiency on cerebral health and function

In the previously explored studies, estrogen's crucial role was elucidated in neurological regulation via ERs, such as synaptic plasticity, neurogenesis, and gene expression. Menopause, marked by the natural decline of ovarian function and circulating blood estrogen levels, significantly influences brain health. The menopausal transition typically unfolds gradually, beginning with alterations in the menstrual cycle, and is medically defined as “Perimenopause”. Most women experience menopause between the ages of 45 and 55 years, marking a natural aspect of biological aging^[101]. The transition to menopause is concomitant with an increased risk of neurovascular diseases, worsened stroke outcomes, and cognitive decline primarily attributed to the loss of estrogen's neuroprotective, anti-inflammatory, vasodilatory, and metabolic effects on cerebral blood vessels^[16].

Experimental studies have provided mechanistic insights into these effects. Gannon et al. investigated vascular cognitive impairment and dementia (VCID) in C57BL/6J female mice utilizing unilateral carotid artery occlusion and chemically induced menopause with 4-vinylcyclohexene diepoxide^[102]. The study reported that menopausal mice exhibited increased weight gain, glucose intolerance, and visceral adiposity, alongside cognitive deficits, particularly when combined with VCID. Impairments in episodic-like memory (NOR) and activities of daily living (nest building) correlated with decreased myelin basic protein (MBP) expression in the corpus callosum, suggesting white matter alterations. Moreover, cognitive deficits were exacerbated, with increased GFAP expression in the cortex, highlighting menopause's detrimental impact on brain function in VCID. Despite these effects, no significant group differences were observed in estrogen receptor (ERα, ERβ, and GPER1) expression in the hippocampus or cortex^[102].

Further research underscores the significant influence of menopause on neuroinflammation and estrogen receptor activity. Benedusi et al. provided critical insights demonstrating that ER activity declines with age in the hippocampus of OVX C57BL/6 repTOP-ERE-Luc mice^[103]. Ovariectomy triggered age-dependent increases in inflammatory mediators (TNF-α, IL1β) and altered glial cell morphology, exacerbating neuroinflammation^[103]. Further emphasizing these findings, Tantipongpiradet et al. found that treatments targeting estrogen deficiency can mitigate menopause-induced alterations^[104]. Ovariectomy resulted in decreased hippocampal neurogenesis, as evidenced by a reduction in doublecortin (DCX)-immunopositive cells, correlating with depressive-like behaviors in OVX mice, which exhibited increased immobility in both the tail suspension test and forced swim test. Additionally, ovariectomy elevated serum corticosterone levels, indicating hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. Treatment with 17β-estradiol and puerarin effectively reversed these elevations and restored brain-derived neurotrophic factor (BDNF) expression, thus promoting neurogenesis in the hippocampus. These findings underscore the potential of estrogenic treatments to mitigate OVX-induced neurobiological alterations and depressive-like behaviors^[104].

The impact of estrogen deficiency on neuroimmune function has also been explored. Sanchez et al. also showed that OVX in female C57BL/6 mice increased anxiety-like behaviors, reduced social interaction, and decreased sucrose preference following LPS administration, and estradiol replacement was shown to mitigate these effects^[105]. The absence of estrogens led to the downregulation of the microglial receptor Cx3cr1, disinhibiting microglial responses to immune stimuli. Furthermore, estradiol treatment reduced elevated proinflammatory markers Il1b and Il6 in OVX mice post-LPS challenge, which indicated heightened neuroinflammatory responses. Although OVX increased microglial density in the CA1 and dentate gyrus regions of the hippocampus, there were no significant changes in microglial morphology. These results indicated that estrogen loss primed microglia, resulting in heightened neuroimmune responses and increased susceptibility to negative affective behaviors^[105].

In addition to immune and cognitive effects, estrogen deficiency influences brain metabolism and oxidative stress. Gaignard et al. reported that young adult female C57BL/6J mice exhibit lower oxidative stress and higher NADH-linked respiration rates in the brain compared to males. This was associated with increased pyruvate dehydrogenase complex activity, which was significantly higher in females but decreased following OVX, suggesting that estrogen contributes significantly to mitochondrial efficiency and redox balance in the female brain^[106].

In parallel, recent clinical studies on postmenopausal women have shown significant findings of menopause on the hemodynamics of CBF. A cross-sectional study of 185 subjects, including premenopausal, and perimenopausal, postmenopausal women, and men, utilized arterial spin labeling MRI to assess CBF. The study found that premenopausal women had higher CBF across various brain regions compared to their perimenopausal and postmenopausal counterparts. The latter groups showed more white matter hyperintensities and exhibited declines in CBF with age, whereas premenopausal women experienced a slight increase in CBF with age^[107] [Table 4].

Influence of estrogen and age on cerebrovascular function and neuroprotection modulation

The mammalian brain regulates CBF through a mechanism called neurovascular coupling, or functional hyperemia, which adjusts regional CBF to meet the metabolic demands of activated brain regions. This response often exceeds metabolic needs, facilitating efficient oxygen diffusion to distant brain cells. Various cell types in the neurovascular unit, including astrocytes, vascular smooth muscle cells, pericytes, and endothelial cells, contribute to this process. Mural cells, in particular, control vessel diameter and blood flow through their contractile properties^[108].

Aging is closely associated with endothelial dysfunction and reduced cerebral blood flow, indicating a significant potential for interactions between age and estrogen in regulating cerebrovascular function. Recent studies in intact SD rats show that both age and sex significantly influence cerebrovascular reactivity, particularly in older female rats, which exhibit reduced production of prostacyclin (PGI2) and thromboxane A2 (TXA2) in the middle cerebral artery (MCA). Research focused on perimenopausal and postmenopausal female rats indicates that estrogen plays a crucial role in regulating vasoconstrictor responses to vasopressin (VP) and exerts opposing effects on cerebrovascular function with advancing age. One of major finding is that estrogen treatment produced age-dependent divergent effects on VP-induced cerebrovascular vasoconstriction. Moreover, age determines the specific cyclooxygenase (COX) isoforms and resulting prostanoids produced under estrogen influence. The study revealed age-related shifts in the types of COX isoforms and prostanoids affected by estrogen. Younger rats have a higher role of COX-1-derived dilatory prostanoids (PGI2), while older rats exhibit increased COX-2-derived constrictor prostanoids (TXA2). Lastly, VP-stimulated PGI2 and TXA2 production increased in both multi-gravid adult (MA) and reproductively senescent (RS) rats. However, in older RS rats with estrogen replacement, VP-stimulated PGI2 production decreases, and TXA2 increases. In OVX MA rats with estrogen replacement, vasoconstriction decreases, and dilator prostanoid function increases. Conversely, in older OVX RS rats with estrogen replacement, vasoconstriction increases along with constrictor prostanoid function^[109].

In addition to understanding estrogen's role in cerebrovascular function across different ages, further investigation into dendritic spines and neuroplasticity in the prpTDP-43A315T mouse model of Amyotrophic Lateral Sclerosis (ALS) reveals that estrogen significantly influences synaptic plasticity. Two-photon live imaging showed that male TDP-43 mice exhibit diminished dendritic spine remodeling capacity compared to wild-type males. Conversely, female TDP-43 mice displayed increased remodeling capacity, with peak plasticity coinciding with elevated estrogen levels during the estrous cycle. Estrogen manipulation through ovariectomy and subsequent E2 replacement influenced spine density and alleviated disease severity. High circulating estrogen levels appear to protect female TDP-43 mice from dendritic spine deficits, increasing spine turnover in a dose-dependent manner and potentially mitigating ALS-like symptoms^[110].

In vitro studies by Ghisletti et al. identified a novel mechanism by which estrogen inhibits NF-κB activation, a key player in inflammation^[111]. E2, in particular, prevents the nuclear transport of NF-κB in macrophages by inhibiting its intracellular trafficking rather than suppressing Iκ-Bα degradation, which is the target of most anti-inflammatory drugs. This effect is mediated through the estrogen receptor ERα via a nongenomic pathway involving PI3K activation. Notably, E2 rapidly induces PIP3 production, indicating that E2 modulates early inflammatory responses through lipid signaling at the plasma membrane. These findings indicate that E2 could serve as a unique anti-inflammatory agent, especially in contexts where chronic inflammation is prevalent, such as postmenopause. The study also highlights that common selective estrogen receptor modulators (SERMs), such as raloxifene and tamoxifen, may not replicate E2’s anti-inflammatory benefits in vivo, pointing to the need for selective modulators that mimic these specific E2 activities without unwanted side effects^[111].

Findings also reveal the neuroprotective potential of SERMs in mitigating damage caused by cerebral ischemia. A study involving OVX adult Holtzman SD female rats indicated that raloxifene enhanced neurogenesis after middle cerebral artery occlusion (MCAO), while tamoxifen did not. Low-dose estrogen also significantly increased neurogenesis at day 5 post-MCAO. Neural progenitor cells migrated to injured areas (cortex and striatum) after MCAO, with E2 and raloxifene treatment increasing BrdU⁺ cells in these regions. Both raloxifene and tamoxifen, along with estrogen, significantly reversed ischemia-induced spine density loss in the cerebral cortex^[112] [Table 5].

Impact of estrogen therapy on maintaining cerebral homeostasis

Cognitive impairment is increasingly recognized as a common consequence of MI, affecting 30%-50% of patients in the long term^[113]. Data show that that approximately 50% of older MI patients experience some form of cognitive impairment within 1 month to 1 year after MI and about 25% develop moderate to severe cognitive impairment as early as 1 month post-discharge^[114]). This cognitive decline is not solely due to the infarct itself but often reflects broader vascular pathology, such as systemic atherosclerosis, cerebral small vessel disease, and chronic hypoperfusion^[115]. Comorbidities like diabetes and hypertension further exacerbate cognitive decline through mechanisms such as oxidative stress, endothelial dysfunction, and neuroinflammation^[116,117]. In this context, estrogen has been shown to exert neuroprotective effects by reducing neuroinflammation, preserving CBF, and promoting synaptic health^[118]. However, translating these potential benefits into clinical practice remains challenging.

A key concept of estrogen therapy is the “critical window” hypothesis, which suggests that estrogen replacement therapy (ERT) may only be beneficial if initiated early after menopause^[119,120]. However, systemic risks associated with ERT, such as thrombotic events and cancer, have limited its widespread adoption. Therefore, SERMs, such as raloxifene and bazedoxifene, have emerged as safer alternatives that may offer neuroprotective effects without the same systemic risks^[121-123]. These developments highlight the importance of refining hormonal treatments and tailoring them to the specific cardiovascular and neurocognitive risk profiles of post-MI women.

Recent studies have explored how estrogens and their receptor modulators influence brain homeostasis after cardiovascular events, with a particular focus on reducing Aβ accumulation, preventing tau hyperphosphorylation, and mitigating oxidative stress and inflammatory cytokine production^[118,124]. These neuroprotective effects are mediated by estrogen receptors ERα, ERβ, and GPER1, which activate signaling pathways such as PI3K/Akt and MAPK/ERK, promoting neuronal survival, synaptic plasticity, and mitochondrial stability^[111,124].

A promising approach in estrogen therapy is the development of brain-targeted estrogen treatments, including prodrugs such as 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), which is administered systemically but converted to 17β-estradiol in the brain. These therapies have shown promise in improving cognitive function without peripheral side effects, suggesting a viable route for clinical translation^[125]. As these findings indicate, personalized, phase-specific hormonal interventions may offer significant benefits in improving cognitive outcomes in women recovering from MI.

Despite these advantages, clinical observations reveal that some postmenopausal women on HRT still experience cognitive decline following MI. This inconsistency may be explained by the “timing hypothesis”, according to which initiation of HRT close to menopause confers neuroprotective benefits, while late initiation may be ineffective or even harmful. In support of this hypothesis, a neuroimaging study revealed that women who started HRT after the age of 60 had increased deposition of tau, a hallmark of AD, underlining the crucial importance of treatment timing^[126].

In men, the role of estrogen is more complex and less well understood. While low levels of endogenous estrogen can promote cognition and vascular function, excessive levels of estrogen or exogenous supplementation can upset the androgen-estrogen balance. Animal studies have shown that high estrogen levels impair reproductive behavior and spatial learning in males^[127,128]. Furthermore, sex-specific differences in estrogen receptor expression and downstream signaling pathways likely mediate divergent neurocognitive outcomes, emphasizing the need for sex-specific hormone therapies following MI.

Furthermore, the role of estrogen in cognitive health is well documented in AD. ERT is widely used to manage menopausal symptoms, and its potential to delay the onset of AD in postmenopausal women is a key area of research. Estrogen has been shown to act as a neuroprotective agent in AD by reducing Aβ and glutamate toxicity, enhancing synaptic plasticity, preserving neurotrophic factors, and decreasing tau hyperphosphorylation. For example, in female OVX mice, ERT prevents tau pathology, likely through its antioxidant properties^[129,130]. Aβ, a key molecular player in AD, forms neuritic plaques that promote disease progression^[131].

The “critical window” for ERT in postmenopausal women with AD reinforces the need for rapid intervention. Studies have shown that early estradiol treatment after OVX in a mouse model of AD (APP/PS1) prevents cognitive decline, inhibits Aβ accumulation, and restores telomerase activity, thereby improving cognitive performance^[132,133]. Conversely, late estradiol treatment offers limited benefits, highlighting the importance of timing for therapeutic efficacy^[133].

In addition, estrogen’s impact on neurogenesis has been studied after stroke. In studies with APP/Ar^+/- and APP/OVX mice, early treatment with estradiol significantly reduced Aβ production and plaque formation, while increasing neprilysin (NEP) activity, thereby facilitating Aβ clearance. Late treatments were less effective, highlighting the importance of early intervention for optimal outcomes^[134].

Estrogen’s neuroprotective effects extend beyond Aβ and tau pathology. In OVX mice subjected to global cerebral ischemia, estradiol treatment mitigated hippocampal CA1 neuronal damage and improved learning and memory function. These effects were absent in long-term estrogen-deprived mice, linking the loss of estrogen to diminished cognitive protection^[135]. Supporting this, 5-bromo-2′-deoxyuridine labeling studies (BrdU⁺ cells) demonstrated that early estrogen replacement significantly increased the proliferation and survival of newly generated neurons in the dentate gyrus and subventricular zone of the brain, after ischemia, correlating with improved spatial memory and behavioral recovery^[136].

Further investigating the timing of estrogen treatment, revealed that early estradiol administration significantly attenuated cognitive deficits in an AD mouse model (Aβ1-42), by increasing hippocampal neurogenesis and reducing markers of oxidative stress^[137]. Importantly, early treatment also activated survival pathways and reduced gliosis, synaptic damage, and proinflammatory cytokines, whereas late treatment failed to deliver similar benefits^[137].

A more recent study highlights the importance of optimizing both the timing and delivery method of estrogen therapy to enhance its therapeutic efficacy while minimizing systemic side effects. Researchers investigated whether delivering estrogen exclusively to the brain could enhance cognitive performance in postmenopausal mice without peripheral adverse effects. Using a surgical menopause model, they treated young and middle-aged ovariectomized C57BL/6J female mice with the brain-selective prodrug DHED. DHED significantly improved spatial in young mice and enhanced both spatial and working memory in middle-aged mice. Importantly, unlike traditional estrogen therapies, DHED did not affect body weight, uterine weight, or visceral fat. These results highlight the potential of brain-targeted estrogen administration as a practical and safer alternative, and support the goal of refining the therapeutic window and route of administration for post-MI estrogen treatment^[119] [Table 6] [Figure 2].

Figure 2. The Role of Estrogen in Cardiac and Brain Cellular Mechanisms: Impacts on Health and Disease. This illustration highlights the effects of E2 on cardiac and brain cells via ER-mediated pathways. In cardiac cells, estrogen enhances vasodilation through NO signaling, reduces fibrosis by upregulating VEGF and Lyve-1, and lowers LDL levels via ApoB-100 regulation. Conversely, it inhibits detrimental effects, such as superoxide and TNF-α production, while modulating Ca²⁺ accumulation in mitochondria. In brain cells, E2 promotes neuroprotection by increasing hippocampal neurogenesis (via BDNF) and synaptic plasticity (PSD95) while supporting vasodilation (PGI2). It mitigates neuroinflammatory responses by inactivating microglia (Cx3CR1), suppressing proinflammatory cytokines (TNF-α, IL-1β, IL-6), and enhancing Aβ degradation through NEP regulation. Additionally, estrogen inhibits apoptotic pathways by decreasing cytochrome c release and caspase activation. These pathways demonstrate estrogen's role in reducing oxidative stress, balancing mitochondrial function, and influencing gene expression to protect against cardiovascular and neurodegenerative diseases. E2: Estrogen; ER: estrogen receptor; NO: nitric oxide; VEGF: vascular endothelial growth factor; Lyve-1: Lymphatic vessel endothelial hyaluronan receptor 1; LDL: low-density lipoprotein; ApoB: Apolipoprotein B; TNF-α: tumor necrosis factor alpha; BDNF: brain-derived neurotrophic factor; PSD95: postsynaptic density 95; PGI2: prostaglandin I2; Cx3CR1: CX3C chemokine receptor 1; IL-1β: interleukin-1beta; IL-6: interleukin-6; Aβ: amyloid beta; NEP: neprilysin. Created in BioRender. Zouein, F. (2025), Available from: https://BioRender.com/oicbvbg.