madman
Super Moderator
ABSTRACT
Cardiovascular diseases (CVDs) are the leading cause of death worldwide. CVDs are promoted by the accumulation of lipids and immune cells in the endothelial space resulting in endothelial dysfunction. Endothelial cells are important components of the vascular endothelium, that regulate the vascular flow. The imbalance in the production of vasoactive substances results in the loss of vascular homeostasis,leading the endothelial dysfunction. Thus, endothelial dysfunction plays an essential role in the development of atherosclerosis and can be triggered by different cardiovascular risk factors. On the other hand, the 17β-estradiol (E2) hormone has been related to the regulation of vascular tone through different mechanisms.Several compounds can elicit estrogenic actions similar to those of E2. For these reasons, they have been called endocrine-disrupting compounds (EDCs). This review aims to provide up-to-date information about how different EDCs affect endothelial function and their mechanistic roles in the context of CVDs.
INTRODUCTION
ENDOTHELIAL DYSFUNCTION
The endothelium is a single layer of endothelial cells (ECs) that lines the inside of blood vessels. It is an active tissue that plays a crucial role in the maintenance of vascular homeostasis (Sandoo, van Zanten et al. 2010). The endothelium has an important role in cardiovascular physiology and pathophysiology by regulating vascular tone, coagulation, fluid exchange, inflammation, and angiogenesis, among other processes (Panza, Quyyumi et al. 1990, Marti, Gheorghiade et al. 2012,Maldonado, Morales et al. 2022). Damage to the endothelium leads to endothelial dysfunction, which is a predisposing factor for atherosclerotic layer formation that allows the development of various cardiovascular diseases (CVDs) such as myocardial infarction and stroke (Medina-Leyte, Zepeda-Garcia et al. 2021,Björkegren and Lusis 2022).
Endothelial dysfunction is a pathophysiological process caused by chronic exposure to different risk factors including toxins, immune alterations, diabetes, hypertension, dyslipidemias, oxidative stress, and smoking, among others (Jeon 2021). These factors produce changes in the permeability of the endothelial layer, leading to the infiltration of low-density lipoproteins (LDL) into the tunica intima layer of the endothelium. Subsequently, LDLs undergo oxidation, which enhances the process of endothelial dysfunction. As a consequence, the vascular surface becomes prothrombotic displaying a pro-inflammatory cellular and humoral environment (Jiang, Zhou et al. 2022). In addition, there is an exacerbated production of adhesion proteins that leads to the recruitment of monocytes, lymphocytes, and platelets, as well as changes in the tissue micro structure (Medrano-Bosch, SimonCodina et al. 2023). These physical, cellular, and biochemical modifications enhance the proinflammatory response, leading to chronic inflammation. In addition,recruited monocytes are activated by macrophages, which engulf oxidized LDLs.These activated macrophages also lead to foam cells that undergo apoptosis and release cholesterol particles, further enhancing the inflammatory state of the endothelium (Gui, Zheng et al. 2022). All these mechanisms contribute to endothelial damage, inducing the migration of smooth muscle cells from the tunica media to the tunica intima, and promotion the secretion of collagen, which stabilizes the atheroma layer, (Figure 1) (Jiang, Zhou et al. 2022).
As a final event, endothelial dysfunction leads to loss of homeostasis with a significant reduction in vasodilator agents such as nitric oxide (NO), a sustained inflammatory response, increased vascular permeability, alterations in angiogenesis, and increased production of adhesion proteins. For these reasons,endothelial dysfunction might be considered a marker of subclinical atherosclerosis (Hadi, Carr et al. 2005).
It is important to mention that for the study of endothelial alterations including endothelial dysfunction and cardiovascular-associated pathologies, several studies have proposed the human umbilical cord as a useful methodological strategy (Mangana, Lorigo et al. 2021). The above is because the umbilical cord is an accessible source for ECs isolation. In addition, this model does not need specific ethical consent since there is no harm to the donors and it is considered a non tumorigenic and less immunogenic model. Also, as a primary culture, the ECs derived from the human umbilical cord maintain native characteristics of endothelial tissue and its intracellular signaling pathways (Medina-Leyte, Domínguez-Pérez et al. 2020).
THE ROLE OF ESTROGENS IN ENDOTHELIAL FUNCTION
Estrogens are the principal sex steroid hormones produced from cholesterol in the ovaries, placenta, breast, adrenal glands, and peripheral adipose tissues in women as well as in the testis, adrenal glands, and peripheral adipose tissues in men(Heldring, Pike et al. 2007). Serum estradiol (E2) levels are approximately 4 times higher in women than men. E2 is considered the most potent estrogen hormone in comparison to estriol, and estrone. Generally, E2 can promote the expression of genes by genomic mechanisms, through its interaction with the nuclear estrogen receptors (ERα and ERβ), as well as non-genomic mechanisms, with the binding to the estrogen membrane-bound receptor, G protein-coupled estrogen receptor 30 (GPER1), which rapidly activates intracellular signaling. Both routes regulate the expression of different molecular targets (Fuentes and Silveyra 2019). While E2 is responsible for the control of the female reproductive system, it also has pleiotropic effects in different organs (Knowlton and Lee 2012, Fuentes and Silveyra 2019).
On the other hand, one of the indications to postulate that E2 has an important role in endothelial homeostasis is the fact that women in menopausal stages have exacerbated effects and symptoms for different CVDs in comparison with their reproductive age counterparts (Mathews, Subramanya et al. 2019). Several cellular and animal experimental strategies, have shown E2 endothelial modulation role associated with the atherosclerotic process. In this sense, E2 promotes the upregulation of nitric oxide synthase (NOS) via both genomic and nongenomic mechanisms, increasing the levels of one of the most potent vasodilator agents, nitric oxide (NO) (Hayashi, Yamada et al. 1995, McNeill, Zhang et al. 2002). Additionally, E2 actions are often associated with the decrease of pro-inflammatory cytokines and chemokines involved in monocyte migration into the subendothelial space, the modulation of low-density lipoprotein (LDL) oxidation, a decrease the endothelial permeability, cellular apoptosis, the production of reactive oxygen species (ROS), and an increase in proliferation of endothelial cells (Cho, Ziats et al.1999, Wagner, Schroeter et al. 2001, Florian and Magder 2008, Oviedo, Sobrino et al. 2011, Chakrabarti, Morton et al. 2014).
*ENDOCRINE-DISRUPTING COMPOUNDS IN THE ENDOTHELIUM
*Cell viability/apoptosis
*Pro-inflammatory cytokines
*Vascular tone
*Interrelation between adhesion proteins in endothelial cells and vascular smooth muscle cells
*Atherogenic process/lipoprotein oxidation
*Oxidative stress
*CLINICAL EVIDENCE
CONCLUSION
This review exposes the mechanisms by which bisphenols, parabens, and phthalates cause endothelial dysfunction, predisposing to different CVDs. It is evident that the mechanisms by which these compounds act are multiple. The damage they cause has even been reported at the clinical level, not only in the adult population but also in the extremes of life, children, and older people. Therefore, itis necessary to disseminate the information to avoid its consumption and/or unnecessary exposure.
In addition, it is necessary to generate new lines of research jointly exposing compounds that allow counteracting the harmful effects of EDCs. In the new generations of toxicologists and medical doctors, it should be required to include notions about the mechanisms these compounds impact and the pharmacological conditions in the therapeutics they may present.
It is even important to consider an emerging concept, such as indirect exposure to EDCs not only synthetic but also natural EDCs within a patient's clinical history, considering individuals close to a family and social environment as distribution vectors. Moreover, considerations of sex, gender, and hormonal status should be included in the research design and data interpretation, to evaluate mechanisms involving hormone receptors and potential implications for sex-specific effects.
Cardiovascular diseases (CVDs) are the leading cause of death worldwide. CVDs are promoted by the accumulation of lipids and immune cells in the endothelial space resulting in endothelial dysfunction. Endothelial cells are important components of the vascular endothelium, that regulate the vascular flow. The imbalance in the production of vasoactive substances results in the loss of vascular homeostasis,leading the endothelial dysfunction. Thus, endothelial dysfunction plays an essential role in the development of atherosclerosis and can be triggered by different cardiovascular risk factors. On the other hand, the 17β-estradiol (E2) hormone has been related to the regulation of vascular tone through different mechanisms.Several compounds can elicit estrogenic actions similar to those of E2. For these reasons, they have been called endocrine-disrupting compounds (EDCs). This review aims to provide up-to-date information about how different EDCs affect endothelial function and their mechanistic roles in the context of CVDs.
INTRODUCTION
ENDOTHELIAL DYSFUNCTION
The endothelium is a single layer of endothelial cells (ECs) that lines the inside of blood vessels. It is an active tissue that plays a crucial role in the maintenance of vascular homeostasis (Sandoo, van Zanten et al. 2010). The endothelium has an important role in cardiovascular physiology and pathophysiology by regulating vascular tone, coagulation, fluid exchange, inflammation, and angiogenesis, among other processes (Panza, Quyyumi et al. 1990, Marti, Gheorghiade et al. 2012,Maldonado, Morales et al. 2022). Damage to the endothelium leads to endothelial dysfunction, which is a predisposing factor for atherosclerotic layer formation that allows the development of various cardiovascular diseases (CVDs) such as myocardial infarction and stroke (Medina-Leyte, Zepeda-Garcia et al. 2021,Björkegren and Lusis 2022).
Endothelial dysfunction is a pathophysiological process caused by chronic exposure to different risk factors including toxins, immune alterations, diabetes, hypertension, dyslipidemias, oxidative stress, and smoking, among others (Jeon 2021). These factors produce changes in the permeability of the endothelial layer, leading to the infiltration of low-density lipoproteins (LDL) into the tunica intima layer of the endothelium. Subsequently, LDLs undergo oxidation, which enhances the process of endothelial dysfunction. As a consequence, the vascular surface becomes prothrombotic displaying a pro-inflammatory cellular and humoral environment (Jiang, Zhou et al. 2022). In addition, there is an exacerbated production of adhesion proteins that leads to the recruitment of monocytes, lymphocytes, and platelets, as well as changes in the tissue micro structure (Medrano-Bosch, SimonCodina et al. 2023). These physical, cellular, and biochemical modifications enhance the proinflammatory response, leading to chronic inflammation. In addition,recruited monocytes are activated by macrophages, which engulf oxidized LDLs.These activated macrophages also lead to foam cells that undergo apoptosis and release cholesterol particles, further enhancing the inflammatory state of the endothelium (Gui, Zheng et al. 2022). All these mechanisms contribute to endothelial damage, inducing the migration of smooth muscle cells from the tunica media to the tunica intima, and promotion the secretion of collagen, which stabilizes the atheroma layer, (Figure 1) (Jiang, Zhou et al. 2022).
As a final event, endothelial dysfunction leads to loss of homeostasis with a significant reduction in vasodilator agents such as nitric oxide (NO), a sustained inflammatory response, increased vascular permeability, alterations in angiogenesis, and increased production of adhesion proteins. For these reasons,endothelial dysfunction might be considered a marker of subclinical atherosclerosis (Hadi, Carr et al. 2005).
It is important to mention that for the study of endothelial alterations including endothelial dysfunction and cardiovascular-associated pathologies, several studies have proposed the human umbilical cord as a useful methodological strategy (Mangana, Lorigo et al. 2021). The above is because the umbilical cord is an accessible source for ECs isolation. In addition, this model does not need specific ethical consent since there is no harm to the donors and it is considered a non tumorigenic and less immunogenic model. Also, as a primary culture, the ECs derived from the human umbilical cord maintain native characteristics of endothelial tissue and its intracellular signaling pathways (Medina-Leyte, Domínguez-Pérez et al. 2020).
THE ROLE OF ESTROGENS IN ENDOTHELIAL FUNCTION
Estrogens are the principal sex steroid hormones produced from cholesterol in the ovaries, placenta, breast, adrenal glands, and peripheral adipose tissues in women as well as in the testis, adrenal glands, and peripheral adipose tissues in men(Heldring, Pike et al. 2007). Serum estradiol (E2) levels are approximately 4 times higher in women than men. E2 is considered the most potent estrogen hormone in comparison to estriol, and estrone. Generally, E2 can promote the expression of genes by genomic mechanisms, through its interaction with the nuclear estrogen receptors (ERα and ERβ), as well as non-genomic mechanisms, with the binding to the estrogen membrane-bound receptor, G protein-coupled estrogen receptor 30 (GPER1), which rapidly activates intracellular signaling. Both routes regulate the expression of different molecular targets (Fuentes and Silveyra 2019). While E2 is responsible for the control of the female reproductive system, it also has pleiotropic effects in different organs (Knowlton and Lee 2012, Fuentes and Silveyra 2019).
On the other hand, one of the indications to postulate that E2 has an important role in endothelial homeostasis is the fact that women in menopausal stages have exacerbated effects and symptoms for different CVDs in comparison with their reproductive age counterparts (Mathews, Subramanya et al. 2019). Several cellular and animal experimental strategies, have shown E2 endothelial modulation role associated with the atherosclerotic process. In this sense, E2 promotes the upregulation of nitric oxide synthase (NOS) via both genomic and nongenomic mechanisms, increasing the levels of one of the most potent vasodilator agents, nitric oxide (NO) (Hayashi, Yamada et al. 1995, McNeill, Zhang et al. 2002). Additionally, E2 actions are often associated with the decrease of pro-inflammatory cytokines and chemokines involved in monocyte migration into the subendothelial space, the modulation of low-density lipoprotein (LDL) oxidation, a decrease the endothelial permeability, cellular apoptosis, the production of reactive oxygen species (ROS), and an increase in proliferation of endothelial cells (Cho, Ziats et al.1999, Wagner, Schroeter et al. 2001, Florian and Magder 2008, Oviedo, Sobrino et al. 2011, Chakrabarti, Morton et al. 2014).
*ENDOCRINE-DISRUPTING COMPOUNDS IN THE ENDOTHELIUM
*Cell viability/apoptosis
*Pro-inflammatory cytokines
*Vascular tone
*Interrelation between adhesion proteins in endothelial cells and vascular smooth muscle cells
*Atherogenic process/lipoprotein oxidation
*Oxidative stress
*CLINICAL EVIDENCE
CONCLUSION
This review exposes the mechanisms by which bisphenols, parabens, and phthalates cause endothelial dysfunction, predisposing to different CVDs. It is evident that the mechanisms by which these compounds act are multiple. The damage they cause has even been reported at the clinical level, not only in the adult population but also in the extremes of life, children, and older people. Therefore, itis necessary to disseminate the information to avoid its consumption and/or unnecessary exposure.
In addition, it is necessary to generate new lines of research jointly exposing compounds that allow counteracting the harmful effects of EDCs. In the new generations of toxicologists and medical doctors, it should be required to include notions about the mechanisms these compounds impact and the pharmacological conditions in the therapeutics they may present.
It is even important to consider an emerging concept, such as indirect exposure to EDCs not only synthetic but also natural EDCs within a patient's clinical history, considering individuals close to a family and social environment as distribution vectors. Moreover, considerations of sex, gender, and hormonal status should be included in the research design and data interpretation, to evaluate mechanisms involving hormone receptors and potential implications for sex-specific effects.
