In addition to ligand - mediated activation, the transcriptional activity of a SHR can
also be affected in the absence of its cognate ligands by phosphorylation of the
receptors themselves or of their coregulatory proteins (Figure 2.1 c; see also review
[50] ). Stimulation of cellular activity by growth factors ( GF ), such as epidermal
growth factor ( EGF ) and insulin - like growth factor ( IGF ) - 1 or the intracellular
effector analog 8 - bromo - cAMP (cAMP analogs) can activate SHR transactivation
in a ligand - independent manner accompanied by an increased receptor phos-
phorylation [51 – 53] .
ERs have been found to be phosphorylated at different sites by various
kinase pathways [ mitogen - activated protein kinase ( MAPK )/ extracellular signal -
regulated kinase ( ERK ) 1/2, protein kinase A ( PKA )] after stimulation with
EGF or IGF [54 – 59] . There is also some evidence that PR can be activated in the
absence of progesterone by phosphorylation in response to EGF or cAMP [52] . It
has been reported that AR can be phosphorylated by MAPK and PKA [53, 60] .
Moreover, it has been reported that the phosphorylation of Ser236 by PKA, within
the DBD, regulates the dimerization of ER α [61] .
In addition to the modifi cations of the receptors themselves, nuclear
coregulator proteins can also be phosphorylated by a variety of kinases leading to
altered transcriptional activity of SHRs ( for a review, see [21] ). Phosphorylation
may enhance interaction of coactivators with SHRs, modulate their effi ciency to
recruit histone acetyltransferase complexes, and enzymatic activity. Steroid
receptor coactivator ( SRC ) - 1 contains consensus sequences for ERK1/2, and
EGF stimulation results in ERK1/2 - mediated phosphorylation of SRC - 1, which
potentiates PRb transcriptional activity [62] . Phosphorylation of coactivators can
also lead to their inactivation, which reduces its interaction with SHRs, resulting
in repression of the SHR transactivation [63] .
Receptor Activity and Availability in the Cardiovascular System
ER α expression has been detected in several tissues including cardiovascular
organs, with considerably different expression levels among these tissues [85] .
Although different molecular mechanisms, such as post - transcriptional and trans-
lational, could be involved in the control of ER gene expression in the cell/tissue,
several studies have indicated that the transcription of the ER α gene plays an
important role in regulating the expression of ER α in different tissues. Previous
reports have revealed that the human ER α mRNA is transcribed from at least
seven different promoters with unique 5 ′ - untranslated region s ( UTR s) (A, B, C,
D, E, F and T) (Figure 2.2 ) [86, 87] . These multiple promoters are utilized in a
cell - and tissue - specifi c manner, strongly contributing to the regulation of ER α
expression [88] . For example in endometrium, the predominant 5 ′ - UTR variants
are A and C, whereas C and F are the major forms in ovaries [85] , and only F in
osteoblasts [89] . A recent study indicated the existence of the 5 ′ - UTR or promoter
variants A, B, C and F in the human myocardium; however, variant F is the domi-
nant form (Mahmoodzadeh et al ., personal communication). These results suggest
that the expression of the ER α gene is predominantly controlled by promoter
F in the human heart. It appears that in each cell/tissue, there are a variety of
specifi c factors that interact with the ER α promoter with trans - activating or trans -
repressing functions, which also affect the regulation of transcription of the ER α
gene [90, 91] .
Localization of SHR s in the Heart and Vessels of Rodent and Men
ER, AR and GR have been identifi ed in both vascular endothelial and smooth
muscle cells, as well as in cardiac fi broblasts and myocytes, in human and rodents
[92 – 99] . In the heart of human and rats, ER α was visualized by confocal immu-
nofl uorescence microscopy, and localized to the cytoplasm, sarcolemma and
intercalated disks of cardiomyocytes (Figure 2.3 ) [94, 96, 99] , and in the nuclei
of fi broblasts, endothelial cell s ( EC s) (Figure 2.4 ) and myocytes (Figure 2.3 )
[95, 99] .
Receptor - Independent Effects of Sex Steroids
ERs are considered to mediate the protective effects of 17 β - estradiol on the cardio-
vascular system, including rapid vasodilatation, reduction of vessel wall responses
to injury and decreasing the development of atherosclerosis [77, 100] . However,
the fact, that 17 β - estradiol exhibits these protective effects against vascular injury
in mice that lack either ER α [101] or ER β [102] as well as in double - knockout mice
(ER α
− / −
ER β
− / −
) [103] suggests that the inhibitory effects of 17 β - estradiol may be, at
least in part, ER - independent. Several studies provided evidence that the inhibitory
effects of estradiol on vascular smooth muscle cell ( VSMC ), cardiac fi broblast and
mesangial cell migration, proliferation, and extracellular matrix production are
mediated by a ER - independent mechanisms involving estradiol metabolisms [104 –
106] . These studies showed that the protective effects of estradiol are mediated by
the hydroxylation of estradiol to catecholestradiols, catalyzed by CYP450 isoforms,
followed by methylation of catecholestradiols to methoxyestradiols, catalyzed by
the enzyme catechol - O - methyltransferase. The catecholestradiols and methoxyestra-
diols have little or no affi nity for ERs [104] .
also be affected in the absence of its cognate ligands by phosphorylation of the
receptors themselves or of their coregulatory proteins (Figure 2.1 c; see also review
[50] ). Stimulation of cellular activity by growth factors ( GF ), such as epidermal
growth factor ( EGF ) and insulin - like growth factor ( IGF ) - 1 or the intracellular
effector analog 8 - bromo - cAMP (cAMP analogs) can activate SHR transactivation
in a ligand - independent manner accompanied by an increased receptor phos-
phorylation [51 – 53] .
ERs have been found to be phosphorylated at different sites by various
kinase pathways [ mitogen - activated protein kinase ( MAPK )/ extracellular signal -
regulated kinase ( ERK ) 1/2, protein kinase A ( PKA )] after stimulation with
EGF or IGF [54 – 59] . There is also some evidence that PR can be activated in the absence of progesterone by phosphorylation in response to EGF or cAMP [52] . It
has been reported that AR can be phosphorylated by MAPK and PKA [53, 60] .
Moreover, it has been reported that the phosphorylation of Ser236 by PKA, within
the DBD, regulates the dimerization of ER α [61] .
In addition to the modifi cations of the receptors themselves, nuclear
coregulator proteins can also be phosphorylated by a variety of kinases leading to
altered transcriptional activity of SHRs ( for a review, see [21] ). Phosphorylation
may enhance interaction of coactivators with SHRs, modulate their effi ciency to
recruit histone acetyltransferase complexes, and enzymatic activity. Steroid
receptor coactivator ( SRC ) - 1 contains consensus sequences for ERK1/2, and
EGF stimulation results in ERK1/2 - mediated phosphorylation of SRC - 1, which
potentiates PRb transcriptional activity [62] . Phosphorylation of coactivators can
also lead to their inactivation, which reduces its interaction with SHRs, resulting
in repression of the SHR transactivation [63] .
Receptor Activity and Availability in the Cardiovascular System
ER α expression has been detected in several tissues including cardiovascular
organs, with considerably different expression levels among these tissues [85] .
Although different molecular mechanisms, such as post - transcriptional and trans-
lational, could be involved in the control of ER gene expression in the cell/tissue,
several studies have indicated that the transcription of the ER α gene plays an
important role in regulating the expression of ER α in different tissues. Previous
reports have revealed that the human ER α mRNA is transcribed from at least
seven different promoters with unique 5 ′ - untranslated region s ( UTR s) (A, B, C,
D, E, F and T) (Figure 2.2 ) [86, 87] . These multiple promoters are utilized in a
cell - and tissue - specifi c manner, strongly contributing to the regulation of ER α
expression [88] . For example in endometrium, the predominant 5 ′ - UTR variants
are A and C, whereas C and F are the major forms in ovaries [85] , and only F in
osteoblasts [89] . A recent study indicated the existence of the 5 ′ - UTR or promoter
variants A, B, C and F in the human myocardium; however, variant F is the domi-
nant form (Mahmoodzadeh et al ., personal communication). These results suggest
that the expression of the ER α gene is predominantly controlled by promoter
F in the human heart. It appears that in each cell/tissue, there are a variety of
specifi c factors that interact with the ER α promoter with trans - activating or trans -
repressing functions, which also affect the regulation of transcription of the ER α
gene [90, 91] .
Localization of SHR s in the Heart and Vessels of Rodent and Men
ER, AR and GR have been identifi ed in both vascular endothelial and smooth
muscle cells, as well as in cardiac fi broblasts and myocytes, in human and rodents
[92 – 99] . In the heart of human and rats, ER α was visualized by confocal immu-nofl uorescence microscopy, and localized to the cytoplasm, sarcolemma and
intercalated disks of cardiomyocytes (Figure 2.3 ) [94, 96, 99] , and in the nuclei
of fi broblasts, endothelial cell s ( EC s) (Figure 2.4 ) and myocytes (Figure 2.3 )
[95, 99] .
Receptor - Independent Effects of Sex Steroids
ERs are considered to mediate the protective effects of 17 β - estradiol on the cardio-
vascular system, including rapid vasodilatation, reduction of vessel wall responses
to injury and decreasing the development of atherosclerosis [77, 100] . However,
the fact, that 17 β - estradiol exhibits these protective effects against vascular injury
in mice that lack either ER α [101] or ER β [102] as well as in double - knockout mice
(ER α
− / −
ER β
− / −
) [103] suggests that the inhibitory effects of 17 β - estradiol may be, at
least in part, ER - independent. Several studies provided evidence that the inhibitory
effects of estradiol on vascular smooth muscle cell ( VSMC ), cardiac fi broblast and
mesangial cell migration, proliferation, and extracellular matrix production are
mediated by a ER - independent mechanisms involving estradiol metabolisms [104 –
106] . These studies showed that the protective effects of estradiol are mediated by
the hydroxylation of estradiol to catecholestradiols, catalyzed by CYP450 isoforms,
followed by methylation of catecholestradiols to methoxyestradiols, catalyzed by
the enzyme catechol - O - methyltransferase. The catecholestradiols and methoxyestra-
diols have little or no affi nity for ERs [104] .
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