- Email: [email protected]
Estrogen receptor-β and the cardiovascular system
184
Research Update
mutants is that they involve centrally mediated effects, and the behavioral alterations observed are presumably the result of disruptions in the neural circuitry of aggression and sexual behavior, rather than in the perception of gender (although whether Trp2−/− animals can distinguish gender remains debatable). More puzzling, however, is the absence of maternal aggression in Trp2−/− mice [2]. Maternal aggression is that shown by lactating females to protect their young. It depends on the suckling stimulus of the pups and is directed at any intruder, regardless of gender [3]. The stimulus parameters, neural substrates and hormonal and environmental determinants of maternal aggression have consistently been found to be distinct from those of male–male
TRENDS in Endocrinology & Metabolism Vol.13 No.5 July 2002
aggression. More importantly, removal of the VNO has no effect [5]. So it would seem there is something unusual and not yet understood about the selective removal of the TRP2 channel, and which might involve more than the perception of odors by the VNO. Although much has been learned from phenotypic analysis of transgenic animals, it might be premature to model complex behavioral repertoires, such as sexual behavior and aggression, that have been sculpted not only by millions of years of evolutionary pressure, but also by the selective processes inherent to laboratory animal practices of the last 50–70 years. References 1 Stowers, L. et al. (2002) Loss of sex discrimination and male–male aggression in mice deficient for TRP2. Science 295, 1493–1500
2 Leypold, B.G. et al. (2002) Altered sexual and social behaviors in trp2 mutant mice. Proc. Natl. Acad. Sci. U. S. A. 99, 6376–6381 3 Miczek, K.A. et al. (2001) Aggressive behavioral phenotypes in mice. Behav. Brain Res. 125, 167–181 4 Kumar, A. et al. (1999) Functional dichotomy within the vomeronasal system: Distinct zones of neuronal activity in the accessory olfactory bulb correlate with se specific behaviors. J. Neurosci. 19, RC32 5 Kolunie, J.M. and Stern, J.M. (1995) Maternal aggression in rats: effects of olfactory bulbectomy, ZnSO4-induced anosmia, and vomeronasal organ removal. Horm. Behav. 29, 492–518
Margaret M. McCarthy* Anthony P. Auger Dept of Physiology and Program in Neuroscience, University of Maryland, Baltimore, MD 21201, USA. *e-mail: [email protected]
β and the cardiovascular system Estrogen receptor-β Ellis R. Levin Retrospective studies show that estrogen significantly decreases the development of primary cardiovascular disease in women. The sex steroid lowers prothrombotic proteins and atherosclerosis-promoting lipids, while maintaining healthy vascular endothelial function by stimulating nitric oxide production. There is little research implicating estrogen as an important controller of blood pressure. In this regard, a recent study provides important new β (ERβ β) evidence that the estrogen receptor-β mediates several actions of estrogen on vascular smooth muscle cells. Most strikingly, aged male rats that have a β develop genetic inactivation of their ERβ moderate hypertension. Thus, estrogen action is probably relevant to the regulation of vascular tone in both sexes. Published online: 30 April 2002
Many epidemiological studies have recognized that men develop cardiovascular disease more frequently and at an earlier age than women. However, young women who undergo ovariectomy or postmenopausal women have the dubious distinction of ‘catching up’ with men in this respect. At least 13 large, retrospective epidemiological studies from Scandinavia, Europe and the US have indicated that estrogen use decreases the incidence of primary http://tem.trends.com
cardiovascular disease by ~50%. Similarly, progestin use has been implicated to be neutral or slightly additive to the effects of estrogen in this regard. Recent work from the Heart and Estrogen/ProgestinReplacement Study and other trials indicates that estrogen use might not prevent further cardiovascular events in women who have established disease at the time of instituting sex hormone replacement [1]. We eagerly await the results of the Women’s Health Initiative clinical trials, to determine prospectively if estrogen use decreases the incidence of primary cardiovascular disease. It is unclear whether ERα or ERβ, the two known estrogen receptors, mediate the specific cardiovascular effects of estrogen. It is in this setting that Zhu et al. [2] examined the role of the ERβ in vascular function. Many actions of estrogen in reproductive and nonreproductive organs predominantly occur via binding to ERα. However, ERβ clearly mediates some estrogen actions in the ovary and other tissues. Both ERα and ERβ are expressed in endothelial and vascular smooth muscle cells, and both receptors can mediate the protective effects of estrogen against acute vascular injury. Interestingly, expression of ERβ (but not ERα) is strongly upregulated in the lining of blood vessels that undergo acute vascular injury.
Cardiovascular effects of estrogen action
How might estrogen protect the vasculature and heart from disease? Estrogen favorably alters the lipid profile, decreasing low-density lipoprotein and increasing high-density lipoprotein cholesterol. Estradiol acting through ERα reduces the rapid atherosclerosis that develops in response to a high-fat diet in female mice with a genetically engineered loss of the gene encoding apoprotein-E [3]. At low replacement doses currently in use, estrogen decreases the synthesis of prothrombotic proteins, such as plasminogen activator-1. Estrogen promotes proper endothelial function, in part through stimulating Ca2+-dependent nitric oxide production in endothelial cells [4]. Estrogen can also limit the response to acute vascular injury (such as after angioplasty) in rodent models [5], partly by inhibiting smooth muscle cell migration and proliferation. Paradoxically, estrogen use is associated with an increase in venous thrombotic disease. This most often occurs in women taking higher concentration estrogen preparations and who concomitantly smoke cigarettes. Vascular tone and blood pressure regulation is maintained through the complex interactions of many hormones and amines that constrict (angiotensin, endothelin and norepinephrine) or dilate (bradykinin and natriuretic peptides) the
1043-2760/02/$ – see front matter. Published by Elsevier Science Ltd. PII: S1043-2760(02)00604-5
Research Update
vasculature. There are both endothelindependent and -independent components to vascular tone. The endothelindependent component predominantly reflects endothelial nitric oxide synthase (eNOS) activation, whereas the endothelin-independent component includes inducible nitric oxide synthase (iNOS) action, arising from smooth muscle and other cells. Estrogen is known to activate both forms of NOS, contributing to endothelial-dependent and -independent vasorelaxation. Zhu et al. [2] determined the actions of estrogen on vascular tissues or in whole mice that retained or lacked the gene encoding ERβ, which had been developmentally inactivated. They found that 17β-estradiol (E2) inhibited endothelium-independent vasoconstriction, probably through the stimulation of iNOS synthesis and NO production in smooth muscle cells. The effects were seen after 18–20 h, reflecting a predominant effect on iNOS synthesis, as opposed to more rapid stimulation of iNOS activity. ERα appeared to inhibit basal iNOS production, as extrapolated from iNOS promoter/luciferase reporter studies. Furthermore, in ERβ-depleted aortic rings, estrogen actually augmented phenylephrine-induced vasoconstriction. This is in keeping with the recent observations of Hodgin et al. [4], who showed that in mice bred for inactivation of the
TRENDS in Endocrinology & Metabolism Vol.13 No.5 July 2002
genes encoding both apoprotein-E and eNOS, intact gonadal function resulted in hypertension. Taken together, ERα might mediate the hypertension-promoting actions of estrogen when ERβ or eNOS is perturbed. Zhu et al. also found that ERβ-deleted vascular smooth muscle cells demonstrated abnormalities of K+-channel function, which have been implicated in the control of blood pressure and vascular resistance. What might be the importance of these findings in a pathophysiological sense? Zhu et al. report the fascinating observation that male mice with the ERβ-deletion developed moderately severe hypertension. Female mice that lack ERβ also developed a significant increase in blood pressure. This occurred on an aging background, because the hypertension generally developed after six months. Although no mechanisms to explain this observation were offered, it is possible that a prolonged decrease in iNOS production or K+-channel dysfunction contributes to the phenotype. This might occur after hypertensioncounteracting mechanisms, such as eNOS production (an ERα-regulated event), are reduced in the endothelium with aging. Alternatively, estrogen action at other locations (e.g. the cardiovascular regulatory areas of the central nervous system) could be involved. Uncovering the nature of this defect should lead to an understanding of the differential effects of
185
ERα and ERβ in cardiovascular regulation. It will also be of interest whether subtle dysfunction of ERβ underlies a population of hypertensive humans. In any case, this is the best evidence to date that estrogen plays an important role in the regulation of vascular tone, most strikingly in aged, male rodents. References 1 Hulley, S. et al. (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. J. Am. Med. Assoc. 280, 605–613 2 Zhu, Y. et al. (2002) Abnormal vascular function and hypertension in mice deficient in estrogen receptor-β. Science 295, 505–508 3 Hodgin, J.B. et al. (2001) Estrogen receptor-α is a major mediator of 17β-estradiol’s atheroprotective effects on lesion size in Apoe−/− mice. J. Clin. Invest. 107, 333–340 4 Hodgin, J.B. et al. (2002) Interactions between endothelial nitric oxide synthase and sex hormones in vascular protection in mice. J. Clin. Invest. 109, 541–548 5 Karas, R.H. et al. (1999) Estrogen inhibits the vascular injury response in estrogen receptorβ-deficient female mice. Proc. Natl. Acad. Sci. U. S. A. 96, 15133–15136
Ellis R. Levin VA Long Beach Healthcare System, University of California, Irvine, 5901 E. Seventh Street (11-111I), Long Beach, CA 90822, USA. e-mail: [email protected]
Meeting Report
β-cell biology in the 21st century Ronald Margolis, Maren Laughlin and Carol Renfrew Haft The NIDDK Workshop: β-Cell Biology in the 21st Century: Engineering a Pathway to Greater Understanding was held at the National Institutes of Health, Bethesda, MD, USA from 26 to 28 November 2001.
understanding of β-cell structure, function and physiology, and to explore the options available for further elucidation of the complex web of signaling pathways that are required for proper β-cell function.
Published online: 19 April 2002
Lessons from single genes
Cell signaling in the pancreatic β cell is disrupted in patients with diabetes, resulting in compromised insulin production and/or secretion, and attendant alterations in signaling in many other cells and tissues in the body, including brain, muscle, liver and fat. This workshop on β-cell biology was convened to define the current state of our
Mature onset of diabetes of the young (MODY) is a collection of rare inherited forms of diabetes that results from mutations in single genes. By studying large kindreds of people with various forms of MODY, mutations in the gene encoding glucokinase (GK), an enzyme involved in glucose sensing, and in five factors involved in regulation of β-cell gene transcription, have been identified as both necessary and
http://tem.trends.com
sufficient to cause diabetes [1]. By contrast, type 2 diabetes (T2DM) results from a complex interplay of multiple susceptibility genes and environmental factors. Genetic variations in calpain 10, a ubiquitously expressed cysteine protease, increase the risk for T2DM in certain populations [2]. These polymorphisms are thought to impact the normal function of the β cell. Through the use of transgenic and knockout animal models, Morris White (Joslin Diabetes Center, MA, USA), Morris Birnbaum (University of Pennsylvania, USA) and Sarah Ferber (Tel-Aviv University, Israel) demonstrated that insulin receptor substrates-1/2 (IRS-1/2), the protein kinase Akt2, and the transcription factor PDX-1
1043-2760/02/$ – see front matter. Published by Elsevier Science Ltd. PII: S1043-2760(02)00586-6
Research Update
mutants is that they involve centrally mediated effects, and the behavioral alterations observed are presumably the result of disruptions in the neural circuitry of aggression and sexual behavior, rather than in the perception of gender (although whether Trp2−/− animals can distinguish gender remains debatable). More puzzling, however, is the absence of maternal aggression in Trp2−/− mice [2]. Maternal aggression is that shown by lactating females to protect their young. It depends on the suckling stimulus of the pups and is directed at any intruder, regardless of gender [3]. The stimulus parameters, neural substrates and hormonal and environmental determinants of maternal aggression have consistently been found to be distinct from those of male–male
TRENDS in Endocrinology & Metabolism Vol.13 No.5 July 2002
aggression. More importantly, removal of the VNO has no effect [5]. So it would seem there is something unusual and not yet understood about the selective removal of the TRP2 channel, and which might involve more than the perception of odors by the VNO. Although much has been learned from phenotypic analysis of transgenic animals, it might be premature to model complex behavioral repertoires, such as sexual behavior and aggression, that have been sculpted not only by millions of years of evolutionary pressure, but also by the selective processes inherent to laboratory animal practices of the last 50–70 years. References 1 Stowers, L. et al. (2002) Loss of sex discrimination and male–male aggression in mice deficient for TRP2. Science 295, 1493–1500
2 Leypold, B.G. et al. (2002) Altered sexual and social behaviors in trp2 mutant mice. Proc. Natl. Acad. Sci. U. S. A. 99, 6376–6381 3 Miczek, K.A. et al. (2001) Aggressive behavioral phenotypes in mice. Behav. Brain Res. 125, 167–181 4 Kumar, A. et al. (1999) Functional dichotomy within the vomeronasal system: Distinct zones of neuronal activity in the accessory olfactory bulb correlate with se specific behaviors. J. Neurosci. 19, RC32 5 Kolunie, J.M. and Stern, J.M. (1995) Maternal aggression in rats: effects of olfactory bulbectomy, ZnSO4-induced anosmia, and vomeronasal organ removal. Horm. Behav. 29, 492–518
Margaret M. McCarthy* Anthony P. Auger Dept of Physiology and Program in Neuroscience, University of Maryland, Baltimore, MD 21201, USA. *e-mail: [email protected]
β and the cardiovascular system Estrogen receptor-β Ellis R. Levin Retrospective studies show that estrogen significantly decreases the development of primary cardiovascular disease in women. The sex steroid lowers prothrombotic proteins and atherosclerosis-promoting lipids, while maintaining healthy vascular endothelial function by stimulating nitric oxide production. There is little research implicating estrogen as an important controller of blood pressure. In this regard, a recent study provides important new β (ERβ β) evidence that the estrogen receptor-β mediates several actions of estrogen on vascular smooth muscle cells. Most strikingly, aged male rats that have a β develop genetic inactivation of their ERβ moderate hypertension. Thus, estrogen action is probably relevant to the regulation of vascular tone in both sexes. Published online: 30 April 2002
Many epidemiological studies have recognized that men develop cardiovascular disease more frequently and at an earlier age than women. However, young women who undergo ovariectomy or postmenopausal women have the dubious distinction of ‘catching up’ with men in this respect. At least 13 large, retrospective epidemiological studies from Scandinavia, Europe and the US have indicated that estrogen use decreases the incidence of primary http://tem.trends.com
cardiovascular disease by ~50%. Similarly, progestin use has been implicated to be neutral or slightly additive to the effects of estrogen in this regard. Recent work from the Heart and Estrogen/ProgestinReplacement Study and other trials indicates that estrogen use might not prevent further cardiovascular events in women who have established disease at the time of instituting sex hormone replacement [1]. We eagerly await the results of the Women’s Health Initiative clinical trials, to determine prospectively if estrogen use decreases the incidence of primary cardiovascular disease. It is unclear whether ERα or ERβ, the two known estrogen receptors, mediate the specific cardiovascular effects of estrogen. It is in this setting that Zhu et al. [2] examined the role of the ERβ in vascular function. Many actions of estrogen in reproductive and nonreproductive organs predominantly occur via binding to ERα. However, ERβ clearly mediates some estrogen actions in the ovary and other tissues. Both ERα and ERβ are expressed in endothelial and vascular smooth muscle cells, and both receptors can mediate the protective effects of estrogen against acute vascular injury. Interestingly, expression of ERβ (but not ERα) is strongly upregulated in the lining of blood vessels that undergo acute vascular injury.
Cardiovascular effects of estrogen action
How might estrogen protect the vasculature and heart from disease? Estrogen favorably alters the lipid profile, decreasing low-density lipoprotein and increasing high-density lipoprotein cholesterol. Estradiol acting through ERα reduces the rapid atherosclerosis that develops in response to a high-fat diet in female mice with a genetically engineered loss of the gene encoding apoprotein-E [3]. At low replacement doses currently in use, estrogen decreases the synthesis of prothrombotic proteins, such as plasminogen activator-1. Estrogen promotes proper endothelial function, in part through stimulating Ca2+-dependent nitric oxide production in endothelial cells [4]. Estrogen can also limit the response to acute vascular injury (such as after angioplasty) in rodent models [5], partly by inhibiting smooth muscle cell migration and proliferation. Paradoxically, estrogen use is associated with an increase in venous thrombotic disease. This most often occurs in women taking higher concentration estrogen preparations and who concomitantly smoke cigarettes. Vascular tone and blood pressure regulation is maintained through the complex interactions of many hormones and amines that constrict (angiotensin, endothelin and norepinephrine) or dilate (bradykinin and natriuretic peptides) the
1043-2760/02/$ – see front matter. Published by Elsevier Science Ltd. PII: S1043-2760(02)00604-5
Research Update
vasculature. There are both endothelindependent and -independent components to vascular tone. The endothelindependent component predominantly reflects endothelial nitric oxide synthase (eNOS) activation, whereas the endothelin-independent component includes inducible nitric oxide synthase (iNOS) action, arising from smooth muscle and other cells. Estrogen is known to activate both forms of NOS, contributing to endothelial-dependent and -independent vasorelaxation. Zhu et al. [2] determined the actions of estrogen on vascular tissues or in whole mice that retained or lacked the gene encoding ERβ, which had been developmentally inactivated. They found that 17β-estradiol (E2) inhibited endothelium-independent vasoconstriction, probably through the stimulation of iNOS synthesis and NO production in smooth muscle cells. The effects were seen after 18–20 h, reflecting a predominant effect on iNOS synthesis, as opposed to more rapid stimulation of iNOS activity. ERα appeared to inhibit basal iNOS production, as extrapolated from iNOS promoter/luciferase reporter studies. Furthermore, in ERβ-depleted aortic rings, estrogen actually augmented phenylephrine-induced vasoconstriction. This is in keeping with the recent observations of Hodgin et al. [4], who showed that in mice bred for inactivation of the
TRENDS in Endocrinology & Metabolism Vol.13 No.5 July 2002
genes encoding both apoprotein-E and eNOS, intact gonadal function resulted in hypertension. Taken together, ERα might mediate the hypertension-promoting actions of estrogen when ERβ or eNOS is perturbed. Zhu et al. also found that ERβ-deleted vascular smooth muscle cells demonstrated abnormalities of K+-channel function, which have been implicated in the control of blood pressure and vascular resistance. What might be the importance of these findings in a pathophysiological sense? Zhu et al. report the fascinating observation that male mice with the ERβ-deletion developed moderately severe hypertension. Female mice that lack ERβ also developed a significant increase in blood pressure. This occurred on an aging background, because the hypertension generally developed after six months. Although no mechanisms to explain this observation were offered, it is possible that a prolonged decrease in iNOS production or K+-channel dysfunction contributes to the phenotype. This might occur after hypertensioncounteracting mechanisms, such as eNOS production (an ERα-regulated event), are reduced in the endothelium with aging. Alternatively, estrogen action at other locations (e.g. the cardiovascular regulatory areas of the central nervous system) could be involved. Uncovering the nature of this defect should lead to an understanding of the differential effects of
185
ERα and ERβ in cardiovascular regulation. It will also be of interest whether subtle dysfunction of ERβ underlies a population of hypertensive humans. In any case, this is the best evidence to date that estrogen plays an important role in the regulation of vascular tone, most strikingly in aged, male rodents. References 1 Hulley, S. et al. (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. J. Am. Med. Assoc. 280, 605–613 2 Zhu, Y. et al. (2002) Abnormal vascular function and hypertension in mice deficient in estrogen receptor-β. Science 295, 505–508 3 Hodgin, J.B. et al. (2001) Estrogen receptor-α is a major mediator of 17β-estradiol’s atheroprotective effects on lesion size in Apoe−/− mice. J. Clin. Invest. 107, 333–340 4 Hodgin, J.B. et al. (2002) Interactions between endothelial nitric oxide synthase and sex hormones in vascular protection in mice. J. Clin. Invest. 109, 541–548 5 Karas, R.H. et al. (1999) Estrogen inhibits the vascular injury response in estrogen receptorβ-deficient female mice. Proc. Natl. Acad. Sci. U. S. A. 96, 15133–15136
Ellis R. Levin VA Long Beach Healthcare System, University of California, Irvine, 5901 E. Seventh Street (11-111I), Long Beach, CA 90822, USA. e-mail: [email protected]
Meeting Report
β-cell biology in the 21st century Ronald Margolis, Maren Laughlin and Carol Renfrew Haft The NIDDK Workshop: β-Cell Biology in the 21st Century: Engineering a Pathway to Greater Understanding was held at the National Institutes of Health, Bethesda, MD, USA from 26 to 28 November 2001.
understanding of β-cell structure, function and physiology, and to explore the options available for further elucidation of the complex web of signaling pathways that are required for proper β-cell function.
Published online: 19 April 2002
Lessons from single genes
Cell signaling in the pancreatic β cell is disrupted in patients with diabetes, resulting in compromised insulin production and/or secretion, and attendant alterations in signaling in many other cells and tissues in the body, including brain, muscle, liver and fat. This workshop on β-cell biology was convened to define the current state of our
Mature onset of diabetes of the young (MODY) is a collection of rare inherited forms of diabetes that results from mutations in single genes. By studying large kindreds of people with various forms of MODY, mutations in the gene encoding glucokinase (GK), an enzyme involved in glucose sensing, and in five factors involved in regulation of β-cell gene transcription, have been identified as both necessary and
http://tem.trends.com
sufficient to cause diabetes [1]. By contrast, type 2 diabetes (T2DM) results from a complex interplay of multiple susceptibility genes and environmental factors. Genetic variations in calpain 10, a ubiquitously expressed cysteine protease, increase the risk for T2DM in certain populations [2]. These polymorphisms are thought to impact the normal function of the β cell. Through the use of transgenic and knockout animal models, Morris White (Joslin Diabetes Center, MA, USA), Morris Birnbaum (University of Pennsylvania, USA) and Sarah Ferber (Tel-Aviv University, Israel) demonstrated that insulin receptor substrates-1/2 (IRS-1/2), the protein kinase Akt2, and the transcription factor PDX-1
1043-2760/02/$ – see front matter. Published by Elsevier Science Ltd. PII: S1043-2760(02)00586-6