A decreased number of cells in the pacemaker has been established during aging, and this is related to a decline in gene expression involved in the sinoatrial function, such as changes in many ion channels and ion-homeostasis related genes (Tellez et al., 2011; Mirza et al., 2012; Kane and Howlett, 2018). The heart decreases its electrical conductance with older age and a slower conduction is seen through the atrium and atrioventricular node. Thus, the occurrence of bradycardia and the necessity of an artificial pacemaker system increases, especially in men (Méndez-Bailón et al., 2017; Chamandi et al., 2018).

One plausible explanation for reduced conduction may be the reduced expression of connexins, involved in myocyte cell connections, in addition to electrophysiological changes in the atrial myocytes (Bonda et al., 2016; Jansen et al., 2017). Experiments using ischemia/reperfusion in hearts isolated from mice, demonstrated that expression of mitochondrial connexin-43 has a protective cardiac effect, and that post-ischemic estrogen treatment reduced infarct size while increasing connexin-43 expression in mitochondria. Further, mitochondrial Cx43 displayed a protective role in female hearts leading to a decreased myocardial ischemia/reperfusion compared to that in age-matched males (Wang et al., 2020). Pacemaker nucleus records, obtained in the electric fish Apteronotus leptorhynchus, showed a sex-dimorphism under the influence of steroid hormones (Zupanc, 2020). Pronounced sex-differences in morphology and in the formation of a syncytium by the astrocytes were observed. A larger syncytium area covering the pacemaker cells was present in females, along with greater connexin-43 expression, suggesting a stronger gap-junction in females, compared to males.

Implications coming from sex-related differences in the heart structure also impact cardiac function, such as systolic function, which clinically, may be frequently accessed by the left ventricular ejection fraction (LVEF), a value that is generally higher in women, compared to men (Chung et al., 2006; Tadic et al., 2019). Older women present higher ejection fraction than men, along with higher right ventricular fractional area and a negative global longitudinal strain, besides greater tricuspid regurgitation velocities. Moreover, abnormal ventricular end-diastolic and end-systolic volumes was higher in women than men. However, overall women had better survival outcomes with pulse pressure as a key determinant and, conversely, heart rate and B-type natriuretic peptide were associated with poorer outcome in men (Beale et al., 2019).

Despite some evidence showing increased ejection fraction in aged women, other studies have shown preserved ejection fraction and, therefore, a better knowledge of cardiac structure and function abnormalities during heart failure may help diagnose people with high risk for death due to CVD (Shah et al., 2014; Merrill et al., 2019). In fact, among old patients (49% were women) with preserved ejection fraction, LV hypertrophy and higher pulmonary artery pressure and LV filling pressure were predictive of heart failure, hospitalization and cardiovascular death (Shah et al., 2014).

Cardiac function also differs and men have defects in the systolic pump earlier, while diastolic function is little compromised (Gebhard et al., 2013). On the other hand, women have greater diastolic involvement, greater systolic torsion and LV shortening, in addition to increased ejection fraction (Yoneyama et al., 2012; Gebhard et al., 2013). In older age, the systolic function is reduced, also evidenced by the decreased capacity of the ventricular myocytes to contract (Fannin et al., 2014; Kane and Howlett, 2018).

Diastolic dysfunction has shown to be a hallmark pathological intermediate in the development of HFpEF. In fact, a cohort study in ethnic Asians demonstrated that prevalence of diastolic dysfunction as also others diastolic parameters increase with advanced age and it is greater in women overall than men (Chang et al., 2021).

The maintenance of optimal output involves development of greater systolic stiffness in the LV (Chen et al., 1998). Interestingly, end-systolic elastance is higher, mainly, in older females (Saba et al., 1999; Redfield et al., 2005). The mechanism behind this event may be related to alterations in chamber geometry. Of importance, aging is associated with impaired subendocardial function (Lumens et al., 2006) due to reduced global longitudinal shortening (Støylen et al., 2020) where arterial stiffness is a greater contributor, especially in women (Bell et al., 2017; Yoshida et al., 2020).

Further, female obesity results in heart failure with preserved ejection fraction (HFpEF) (Kitzman and Shah, 2016). This condition occurs due to ischemic events in the heart’s circulation, especially in vessels of large caliber, resulting in reduced contraction of the ventricles (Murphy et al., 2020). This and other evidence show that the occurrence of CVD in obese patients is most dangerous for women. Some mechanisms may explain the association between increased adiposity and HFpEF. Augmented adiposity promotes inflammation which induces dysregulation of the nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling cascade which in turn leads to mitochondrial disruption and endothelial dysfunction (Paulus and Tschöpe, 2013). Additionally, greater activation of the angiotensin-aldosterone signaling pathway can cause myocardial injury (Kitzman and Shah, 2016). Moreover, estrogenic vasodilatory effects as well as myocardial energy substrates changes during post-menopause and they have been proposed as important contributors to the pathogenesis of HFpEF, once its prevalence increases in postmenopausal women (Sabbatini and Kararigas, 2020; Gökçe et al., 2003; Voutilainen et al., 1993).

In fact, hormone therapy (HT) decreased LV mass by 20% in postmenopausal women (Lim et al., 1999) and also reduced LV mass index in hypertensive women (Light et al., 2001). In the same way, ovariectomized animals treated with GPR30 (estrogen receptor) agonist (G1) displayed improved LV diastolic function, collagen deposition, atrial natriuretic factor, cardiac NAD(P)H oxidase 4 (NOX4) expression and, inhibited angiotensin II-induced hypertrophy in H9c2 cardiomyocytes, whereas GPR30 antagonist inhibited the protective effects on this hypertrophy (Wang et al., 2012).

Isolated hearts from both adult female and male rats treated with estradiol leads to the development of cardioprotection against infarction, though a reduced effect was observed in hearts from male rats (Sovershaev et al., 2006). The mechanism behind this protection relies on the activation of the PI3K/GSK3β, favoring mitochondrial protection. Further, estradiol is able to induce S-nitrosylated proteins and greater NO-signaling activation, which are known to be cardioprotective (Deschamps and Murphy, 2009). Estrogen deficiency via ovariectomy (OVX) in hypertensive female rats increases oxidative stress as well as cardiac inflammation which result in diastolic dysfunction and myocardial fibrosis (Mori et al., 2011).

Further, estradiol protects isolated hearts from female SHR against IR injury via GPR30 leading to Nocth-1 activation. Through non-nuclear estrogen receptors, phosphoinositol 3 kinase-dependent and mitochondrial adenosine triphosphate (ATP)-sensitive potassium channels survival (Rocca et al., 2018) leads to endothelial nitric oxide synthase (e-NOS) activation and S-nitrosylation (Shao et al., 2016) which play a key role in post-translational modification in cardioprotection (Menazza et al., 2017).

Although several studies showing a cardio-protective role for premenopausal hormones, conflicting evidence exists regarding the efficacy of hormone therapy in postmenopausal women (Korzick and Lancaster, 2013).

Increased collagen deposition and LV stiffness as well as concentric remodeling are associated with female sex and age (Hoshida et al., 2016). Among the female hormones, estrogen plays a key role during age-related diastolic dysfunction in women. Indeed, this hormone is a vasodilator (Reis et al., 1994) acting at cellular Ca²⁺ handling sites, which could impact diastolic performance (Oneglia et al., 2020). Further, it was demonstrated in rats that OVX decreased expression of phosphorylated phospholamban [PLB (facilitates sarco(endo)plasmic reticulum Ca²⁺-ATPase 2a (SERCA2a) activity)] which in turns reduced lusitropy and increased cardiac filling pressures. Of note, the worst diastolic dysfunction caused by OVX was demonstrated in older rats than middle-age (Alencar et al., 2017). Furthermore, estrogen treatment in a primate model of menopause preserved diastolic function due calcium homeostasis (Michalson et al., 2018).

Another mechanism contributing to diastolic dysfunction is increased oxidative stress (Kumar et al., 2019). Decreased ROS production was seen in female rat heart upon ischemia/reperfusion compared with age-matched male hearts via posttranslational modification of mitochondrial proteins (Lagranha et al., 2010). Indeed, preclinical ischemia/reperfusion studies with OVX demonstrated that estrogen induces ATP production and electron transport chain activity (Lancaster et al., 2012), downregulates mitochondrial apoptotic pathways (Fliegner et al., 2010) and upregulates mitochondrial antioxidants (Liu et al., 2014). Further, this hormone was able to reduce ROS formation, prevent energy dysregulation and improve diastolic function (Chen et al., 2015) in treated OVX mouse model of hypertrophic cardiomyopathy. Of importance, ROS acts as a scavenger to nitric oxide, a key regulator of normal diastolic function (Silberman et al., 2010).

As already mentioned, circulating estrogen and testosterone levels decrease with age and there is a link between sex hormones and CVD. Interestingly, long-term gonadectomy in older male mice slowed isovolumic relaxation time promoting diastolic dysfunction in the aging heart. The mechanism behind this dysfunction may due to higher cardiac expression of PLB protein in older mice with gonadectomy compared to control mice. The increase in PLB interferes with Ca²⁺ uptake, prolonging its uptake in the sarcoplasmic reticulum and prolonged transient Ca²⁺ decay in cardiac cells from aging gonadectomy mice. Further, in hearts from aging gonadectomy mice, there is a reduction in phosphorylation of the regulatory myosin light chain ELC (Ayaz et al., 2019).

Growing evidence has linked polyunsaturated fatty acids (PUFAs) and cardiac homeostasis. PUFAs are metabolized through numerous metabolic pathways, including cytochrome P450 (CYP) monooxygenase (Jamieson et al., 2017). The progression of CVDs such as hypertension and atherosclerosis has been implicated in the hydrolysis and inactivation of epoxy metabolites by soluble epoxide hydrolase (sEH) (Harris and Hammock, 2013). When compared to aged wild-type (WT) mice, male sEH null mice had preserved diastolic function and females had preserved systolic function. Furthermore, the latter preserved Sirt-3 activity, mitochondrial ultrastructure and SOD activity levels. Increased age-related carbonyl levels have been demonstrated in male WT and sEH null mice (Jamieson et al., 2020).

In human, macroscopic changes such as thickening of the aortic valve leaflets, accumulation of lipids and calcification of the aortic valve are observed in both sexes during aging. Carotid intima-media thickening, coronary artery calcification and the formation of atherosclerotic plaques are more prevalent in men than in adult and middle-aged women; however, as they become older, women start to present greater dysfunctions (Kelley et al., 2011; Merz and Cheng, 2016). Men tend to have a higher risk of plaque (Ota et al., 2010; Merz and Cheng, 2016). Interestingly, women with coronary artery disease were less likely to undergo optimal secondary prevention with antiplatelet and lipid-lowering therapies than their male counterparts (Madan et al., 2020).

When considering the scientific evidence on the increased risk of CVD in old age, it is important to consider changes in cardiac functional and structural aspects (Kane and Howlett, 2018). Mortality in the western world is mainly caused by CVDs, a factor that is increasing globally (Heidenreich et al., 2011). In the formation and expansion of plaque in atherosclerosis, senescence inducers, such as telomere shortening and oxidative stress are produced in vascular smooth muscle cells and endothelial cells (Wang and Bennett, 2012). As a result, senescent endothelial cells are prone to apoptosis, endothelial layer “leakiness”, oxidized LDL extravasation and, decreased NO secretion (Hogg and Kalyanaraman, 1999; Zhang et al., 2002; Krouwer et al., 2012). Further, with aging, the vasculature displays alterations such as aortic stiffening and thus, vascular aging may be considered a prodromal stage of atherosclerotic diseases (Zhang et al., 2018).

The incidence of HFpEF and HFrEF in both sexes, increases with age. In women, especially postmenopausal women, there is a higher HFpEF index, while men have a higher prevalence of HFrEF (Beale et al., 2018; Sickinghe et al., 2019). Whereas HFrEF is related to larger vessels developing after an ischemic event (Sickinghe et al., 2019), HFpEF is gradual, involving the microvasculature of the heart (Lee et al., 2016).

A mechanism contributing to this phenomenon may be through 17β-estradiol (E2). In fact, E2 is able to regulate eNOS activity, increase soluble guanylyl cyclase (sGC) to elevate cyclic GMP (cGMP) concentrations leading to activation of protein kinase G (PKG) (Nevzati et al., 2015). Further, E2 also acts via protein kinases PI3K and Akt signaling (Gourdy et al., 2018). Through p38/MAPK signaling, E2 inhibited the proliferation of VSM cells only in female mice (Pellegrini et al., 2014). Furthermore, the inflammatory regulation of the initial atherosclerotic plaque is prevented by the activation of ER-α, decreasing the deposition of lipoproteins and, consequently, the formation of fatty streaks (Elhage et al., 1997).

With aging, perivascular fibrosis (formation of fibrosis around blood vessels) increases (Nosalski et al., 2020) and this fibrosis formation can be influenced by estrogen (Sickinghe et al., 2019). In women, the inhibition of collagen I and III production occurs through activation of ER-α cardiac fibroblasts by E2, whereas in men the E2 to ER-β binding stimulates collagen production (Dworatzek et al., 2019). Cardiac fibrosis in men occurs due to the androgenic influence of the up-regulation of TGF-β, resulting in extracellular matrix deposition (Kong et al., 2014).

Comorbidities such as diabetes, obesity and hypertension share the ability to induce a systemic inflammatory state which was recently shown to be accompanied by a larger deterioration of the cardiac cells function and structure in HFPEF (Mohammed et al., 2012; Paulus and Tschöpe, 2013). In fact, high circulating levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) were observed in a cross-sectional study of HFPEF patients regardless the sex (Kalogeropoulos et al., 2010).

Cellular senescence is heterogeneous and cell specific, triggered by critical stressors including DNA damage, oncogenes, among others (Gliemann et al., 2016). Vascular senescence is a pathophysiological process of structural and functional changes including dysregulation of vascular tone, increased endothelium permeability, arterial stiffness, impairment of angiogenesis and vascular repair (Mitchell et al., 2004).

Vascular endothelial cell (EC) senescence is observed in both inflammation and aging and is associated with vascular dysfunction, leading to CVD in the aging individual (Smulyan et al., 2001). Senescent ECs show attenuated endothelial nitric oxide (NO) production, increased endothelin‐1 (ET-1) production, elevated inflammation, increased expression of adhesion molecules VCAM-1 and ICAM-1 and increased cell apoptosis, as well as increased activation of NF-κB (Colpani and Spinetti, 2019). In fact, a randomized study involving 541 men and women, aged 70–82 years, demonstrated that elevated levels of plasminogen activator and Von Willebrand factor, as markers of EC injury and dysfunction, were associated with lower cerebral blood flow in older adults at high risk for CVD (Mitchell et al., 2004).

Interestingly, a study with cell culture-based bioassay on primary human arterial endothelial cells from both men and women with peripheral artery disease showed that cellular ROS production was higher in women than in men, suggesting increased endothelial oxidative stress (Gardner et al., 2015; Uryga and Bennett, 2016; Jia et al., 2019; Sun and Feinberg, 2021).

The molecular mechanisms involved with vascular stiffness resulting from fibrosis and extracellular matrix are stimulated by vasoactive molecules such as endothelin-1, aldosterone and angiotensin II, commonly associated with aging (Harvey et al., 2016). The pathways related to pathophysiological changes in the vascular endothelium include activation of the transforming growth factor-β1, increased expression and activation of matrix metalloproteinases, galectin-3 overload, SMAD signaling, activation of the renin angiotensin-aldosterone system and, activation of inflammatory and fibrotic signaling pathways (p38 MAPK, TGF-β) (Qi et al., 2011; Yaghooti et al., 2011; Wang et al., 2012; Calvier et al., 2013; Song et al., 2015).

With aging, arterial stiffness increases in both sexes (Mitchell et al., 2004), however, women display a greater stiffening after menopause, which corroborates with the decrease in estrogen levels. Further, with aging, large-artery stiffness and wave reflections increase and this is particularly higher in women (Smulyan et al., 2001; Mitchell et al., 2004). In fact, women taking hormone replacement therapy (HRT) displayed a decrease in the carotid‐femoral PWV (Rajkumar et al., 1997). A study with ovariectomized monkeys showed that 18 months of estrogen treatment was able to reduce arterial stiffness (Adams et al., 1990). Testosterone deficiency in men without CVD is associated with increased carotid-femoral PWV, probably promoting premature vascular aging due to increased arterial stiffness (Vlachopoulos et al., 2014). Another evidence of low testosterone levels is microvascular dysfunction in middle-aged men (Corrigan et al., 2015). Moreover, hypogonadal men who use testosterone replacement therapy show an improvement in arterial stiffness (Yaron et al., 2009).

Wall shear stress is the drag exerted by flowing blood on the vessel wall, playing an important role in the production of vasoactive substances by endothelial cells. Interestingly, a longitudinal observational study reported no significantly differences between sexes regarding mean shear stress in 12 years of observation, however, it was shown that peak shear stress decreases significantly only in men. Further, arterial stiffness increases with aging with women displaying a greater result (+74.5% in women and +28.0% in men) (Irace et al., 2012). In the same way, mean wall shear stress from neck vessels decreased with age and it is significantly higher in females than in males, possibly due to a decrease in flow (Zhao et al., 2015).

In addition, women have less coronary flow reserve than men and have more functional than structural coronary abnormalities (Shaw et al., 2009; Collins et al., 2020). The Working Study Group on micro- and macro- circulation of the Italian Society of Hypertension (SIIA) found that the vascular wall/lumen ratio tends to increase with age in both sexes (Bruno et al., 2018; Rizzoni et al., 2019). Older women have less baroreflex sensitivity than older men, presenting greater carotid artery stiffness (Lacolley et al., 2017). Finally, PWV increases in both sexes, however, it is more pronounced in men over 50 years of age (AlGhatrif et al., 2013). When comparing telomere lengths between men and women, it was found that with advancing age, men with shorter telomeres were more prone to high blood pressure and high PWV values (Laina et al., 2018).

Key mechanisms such as oxidative stress and inflammation may contribute to the vascular aging process via decreased testosterone levels in both women and men (Moreau et al., 2020). Augmented ROS, acting as inflammatory mediators, impair endothelial function and worsen arterial stiffness by decreasing NO production, degrading elastin, and increasing collagen and calcium deposition. Even in apparently healthy adults, aging causes a progressive decline in macro and microvascular endothelial function. Furthermore, there are gender differences in the rate of this decline (Moreau et al., 2020).

In fact, male rats treated with testosterone showed increased antioxidant activity (catalase and superoxide dismutase) which was lost with castration (Ahlbom et al., 2001; Kłapcińska et al., 2008; Eleawa et al., 2013). Similarly, in humans, decreased testosterone concentration was correlated with pro-inflammatory cytokines in older men (Barud et al., 2002; Malkin et al., 2004). Moreover, hypogonadal older men who take testosterone supplementation displayed decreased circulating levels of TNF-α and increased levels of IL-10 (Malkin et al., 2004).

In early and late postmenopausal, high testosterone concentrations elevated levels of inflammatory markers and C-reactive protein (Sowers et al., 2005; Maturana et al., 2008; Maggio et al., 2011). Experiments in ovariectomized (OVX) spontaneously hypertensive rats showed an increased relaxation in aorta after treatment with estrogen compared to OVX rats, however, this protection was abolished when the animals received estrogen plus testosterone, activating NADPH-oxidase subunit p47^phox and consequently increasing the production of superoxide (Costa et al., 2015).

Moreover, infusion of vitamin C (antioxidant) in women who underwent OVX restored vasodilatory responses to acetylcholine (Virdis et al., 2000) and increased FMD in estrogen-deficient postmenopausal women (Moreau et al., 2013). Aerobic exercise increases FMD in older men, but only postmenopausal women who are receiving E2 therapy change, probably due to oxidative stress (Moreau et al., 2013).

Vascular homeostasis is due to the balance between endothelial vasoconstrictor and vasodilator factors, thus, endothelial dysfunction can result in CVD. Adequate NO synthesis and release by endothelial cells are predictors of a good endothelial response to stimuli (Sandoo et al., 2015). The accumulation of oxidative stressors, common during aging, triggers a decrease in the production of NO, and may be responsible for the inactivation of SIRT1. Consequently, this inhibition interferes with the growth of endothelial cells due to the increase in acetylation of p53 (Ota et al., 2010; Cencioni et al., 2013). Greater suppression of NO contributes to arterial stiffness in rodent models and elderly women, reducing endothelium-dependent dilation (Durrant et al., 2009; Donato et al., 2018).

In advanced aging and in both sexes, oxidative stress and inflammation can modulate endothelial dysfunction by raising blood pressure, blood glucose, obesity and sodium intake. Thus, changes in the endothelium may occur even in the absence of a related disease (Donato et al., 2015; Tesauro et al., 2017). However, the main cause of morbidity and mortality in women is CVD (Collins et al., 2020). Differences in vascular pathophysiology between sexes have been identified in current advanced cardiac imaging techniques (Maas et al., 2011). Common conditions among women such as polycystic ovary syndrome, pre-eclampsia, autoimmune diseases, anemia, hyperuricemia and menopause can accelerate atherosclerosis, promoting endothelial dysfunction (Lian and Keaney, 2010; Collins et al., 2020). In pre-menopause, a decrease in endothelial function begins, accompanied by a worsening after menopause or another period of prolonged estrogen deficiency (Bechlioulis et al., 2010; Moreau et al., 2012). During the menopause transition, due to the loss of the antioxidant, anti-inflammatory, anti-proliferative and dilating effects of estradiol on the vascular wall, there is a decrease in endothelial function and an increase in arterial stiffness (Moreau, 2018).

Estrogen influences vascular protection by positively regulating NO (Jespersen et al., 2012; Wanitschek et al., 2016; Collins et al., 2020). Such relationship can be observed in women who have had an ovariectomy, where they develop a reduction in endothelium-dependent dilation (Virdis et al., 2000). In women, estradiol acts on estrogen receptors (ERs) present in the vasculature by releasing NO via eNOS activation through both genomic and non-genomic mechanisms. Moreover, the greater vascular relaxation by estradiol includes greater β-adrenergic and lower α-adrenergic sensitivity (Duckles and Miller, 2010). After menopause, there is an increased risk of CVD due to the loss of this protection and a reduction in the action of the β-adrenergic receptor for vascular tone (Stice et al., 2009).

Another mechanism contributing to sex differences in vascular aging is through mineralocorticoid receptors (MRs) which act in response to aldosterone by modulating renal sodium reabsorption and then regulating blood pressure (Kim et al., 2018). It was demonstrated that vascular stiffness increases with age in both sexes, however, later in life of females, correlating with the timing of increased vascular MR expression. Further, this augmented vascular stiffness is prevented in smooth muscle cell-specific MR deletion (SMC-MR) deficient males and females. Interestingly, vascular fibrosis increases later in life in females and is attenuated by SMC-MR deletion in males only (DuPont et al., 2021). Angiotensin II (Ang II) signaling modulates constriction in the vasculature and is known to increase with aging (Wang et al., 2010). Of importance, MR contributes to Ang II-induced vasoconstriction only in males whereas in females, the mechanisms are distinct (DuPont et al., 2021).

The renin-angiotensin system (RAS) plays an important role in the development of CVD in aging. Recently, angiotensin converting enzyme 2 (ACE2) was shown to produce angiotensin (Strehler, 1977; Hayflick, 2007; De La Fuente, 2008; López-Otín et al., 2013; Davalli et al., 2016; Bai, 2018; Steverson, 2018) [Ang-(1–7)], vasodilator/antiproliferative peptide witch has opposite effects to Ang II (Kim et al., 2018; DuPont et al., 2021).

Ang II promotes cell senenescence in HUVEC culture, by increasing senescence-associated galactosidase, DNA damage and adhesion molecule expression which were inhibited by activation of Ang-(1–7) through G protein-coupled receptor Mas (MasR) (Wang et al., 2010). Additionally, Ang-(1–7) causes vasodilator effects in rats via activation of angiotensin type 2 receptors (AT(2)R). Interestingly, a study demonstrated that aorta from aged rats displayed increased AT(2)R, MasR, and ACE2, suggesting that Ang (Strehler, 1977; Hayflick, 2007; De La Fuente, 2008; López-Otín et al., 2013; Davalli et al., 2016; Bai, 2018; Steverson, 2018)-mediated depressor effects are preserved in aged animals (Rubio-Ruíz et al., 2014).

Further, resveratrol, an antioxidant drug, was able to protect against arterial aging through reduced activity of the ACE-Ang II axis and stimulation of the ACE2-Ang-(1-7)-ATR2-MasR axis (Bosnyak et al., 2012; Santos et al., 2013; Kim et al., 2018; Romero et al., 2019).

Age-related changes in vascular responses to angiotensin-(1–7) were demonstrated in both male and female mice. In this study, the Ang-(1–7) vasodilatory effect was absent in aorta from old females compared to young females, which was restored by estradiol replacement. Further, the treatment was able to decrease production of ROS and normalize levels of NO. Regarding male mice, Ang-(1–7) induced a dose-dependent vasodilator effect in aorta regardless of whether the artery was from young or old mice (Costa-Fraga et al., 2018).

The endothelin system is also impacted by aging and a role in sex difference has been demonstrated. It is well known that endothelin receptors (ETR) mediate vasoconstriction and vasodilation in arteries (Van Guilder et al., 2007). Interestingly, a study evaluating endothelial function in men showed a key role performed by ET_AR in vasodilation and vasoconstriction. In fact, older men displayed blunted responses to acetylcholine which was improved by co-infusion of BQ-123 (ET_AR antagonist), suggesting that, at least in part, reduction in endothelial function with age is through ET_AR (Westby et al., 2011). In contrast, in postmenopausal women endothelial function decline due to a loss of ET_BR-mediated dilation, since ET_BR antagonist (BQ-788) restored vasodilation in postmenopausal women (Wenner et al., 2017).