(Circulation. 1996;94:727-733.)
© 1996 American Heart Association, Inc.
Articles |
Identification of Authentic Estrogen Receptor in Cultured Endothelial Cells
A Potential Mechanism for Steroid Hormone Regulation of Endothelial Function
the Cardiovascular Divisions (C.D.V., A.B.R., D.E.V.), Vanderbilt University Medical Center, and Nashville Veterans Affairs Medical Center (D.E.V.), Nashville, Tenn.
Correspondence to Douglas E. Vaughan, MD, Vanderbilt University Medical Center, Division of Cardiology, Rm 315 MRB II, Nashville, TN 37232-6300. E-mail Doug.Vaughan@mcmail.vanderbilt.edu.
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Abstract |
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Background Estrogen plays a major role in the delayed expression of coronary heart disease (CHD) in women, and recent data indicate that postmenopausal estrogen therapy reduces the incidence of CHD by >40%. The mechanism or mechanisms through which estrogen exerts this benefit are unknown, although effects on blood pressure, carbohydrate and lipid metabolism, and coagulation have been suggested. We hypothesized that at least part of the effect of estrogen in reducing the incidence of CHD is due to an effect on endothelial cell function.
Methods and Results In the present study, we examined human aortic and umbilical vein endothelial cells and bovine aortic endothelial cells for the presence of estrogen receptors (ERs) through immunoblot and mRNA analyses. Electrophoretic mobility shift assays were also performed to determine the DNA-binding properties of the putative ERs. Nuclear extracts from all three endothelial cell types were found to contain a 67-kD protein that reacted with anti-ER monoclonal antibodies specific to different domains of the ERs. Each of these types of cells expresses proteins that bind specifically to consensus estrogen-responsive elements. Finally, Northern blots verified that endothelial cells express abundant amount of mRNA for the ER.
Conclusions These data indicate that endothelial cells constitutively possess the potential for transcriptional regulation of target genes by estrogen. The evolutionary conservation of this receptor in bovine and human endothelial cells suggests a common mechanism for estrogen regulation of endothelial function.
Key Words: endothelium • hormones • receptors • coronary disease
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Introduction |
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The protective effect of endogenous sex hormones is commonly believed to explain the gender gap in the risk of coronary heart disease. Estrogen deprivation results in alterations of plasma lipids, a drop in HDL level, and a rise in LDL level1 ; estrogen replacement therapy reverses these effects by accelerating the metabolism of LDL,2 possibly through ER-mediated transcriptional activation of LDL receptor gene expression.3
The epidemiological data suggest, however, that all of the atheroprotective effects of estrogen cannot be accounted for by alterations in serum lipid profiles.4 5 Recent data point to a positive correlation between ER expression and the absence of atherosclerosis in human coronary arteries.6 Estrogen modulates endothelium-dependent responses of arteries ex vivo,7 8 and its acute administration improves endothelium-dependent vasodilatation in healthy postmenopausal women.9 10 This direct vasodilatory effect of estrogen is rapid in onset and is unlikely to be caused by alterations in gene expression.11 12 Conversely, estrogen may modulate the endothelial expression of rate-limiting enzymes in the biosynthesis of the two important vasodilators prostacyclin and endothelium-derived relaxation factor (NO). A preliminary study indicates that ER causes a 50% increase in constitutive eNOS mRNA levels in HUVEC and induces a sixfold increase in their basal NO production.13 Estrogen also potentiates the effect of endothelin-1 on prostacyclin production in HUVEC.14
The transcriptional regulation of target genes by estrogen requires binding of the ligand to its intracellular receptor, which initiates a sequence of events leading to modulation of gene expression. The estrogen receptor is a hormone-dependent transcription factor that induces or represses transcription of selected genes containing consensus regulatory sequences, referred to as EREs. The classic ER is a 67-kD protein with separate and highly conserved DNA and hormone-binding domains and is coded for by a cDNA that is 6.2 kb long. Shorter and commonly nonfunctional variants of the ER have been described in breast tumor cells15 and, recently, in normal tissues.16 17 It is generally assumed that in vivo, estrogen induces structural changes in its receptor and thus enhances binding to consensus DNA sequences (EREs) and promotes subsequent transcriptional activation. The precise binding of ER to DNA is realized through two Zn2+ binding motifs folded to form a single structural unit.18 EREs are highly conserved palindromic sequences with the characteristic motif GGTCAC(N)3GTGACC.
With regard to vascular tissues, functional ER has been identified in vascular smooth muscle cells,19 and ER presence in endothelial cells had been suggested by estrogen-binding studies.20 21 However, the simple measurement of ER presence through ligand binding does not provide conclusive evidence of its expression or functional potential. In fact, the existence of sex steroid hormone receptors in endothelial cells has been disputed.22 The present study was designed to determine whether ERs can be identified in endothelial cells through the use of specific monoclonal antibodies and molecular probes. Our results confirm the presence of a classic ER in endothelial cells that can bind specifically to a consensus DNA ERE.
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Methods |
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Cell Cultures
HAEC (Cell Systems Co) were grown and maintained in the specific medium supplied by the manufacturer and supplemented with 10% FBS (Hyclone Laboratories). HUVEC and BAEC were prepared as primary cultures and cultivated in Medium 199 (GIBCO-BRL), supplemented with 15% FBS. For treatment with estrogen (10 nmol/L 17-ß estradiol, Sigma Chemical Co), cells were cultivated for
2 days in a phenol red–free medium supplemented with charcoal/dextran–treated serum. The estrogen-responsive rat pituitary cells GH323 (kindly provided by Dr Mark Seyfred, Vanderbilt University) were maintained in DMEM with 10% bovine calf serum. The ER-negative human adenocarcinoma breast cells BT-20 were kindly provided by Dr Fritz Parl (Vanderbilt University).
Protein Extracts
For separation of nuclear and cytosolic fractions, cells were washed once with cold PBS; washed once with buffer containing 20 mmol/L PIPES, pH 6.8, 5 mmol/L MgCl, 1 mmol/L CaCl, 80 mmol/L KCl, 5% sucrose, and the ex tempore added proteinase inhibitors 0.2 mmol/L phenylmethylsulfonyl fluoride, 50 µg/mL aprotinin, 5 µg/mL leupeptin, and 5 µg/mL pepstatin A; resuspended into the same buffer with 0.5% Nonidet P-40; and gently stirred on ice for 5 minutes. Nuclear pellets were collected through centrifugation at low speed, washed once with the same buffer and once without the nonionic detergent, and extracted in a buffer containing 50 mmol/L Tris-HCl, 400 mmol/L NaCl, 10% glycerol, and 1 mmol/L dithiothreitol. The extracts were clarified through a 30-minute centrifugation at 10 000g and stored at -80°C. The cytosolic protein supernatant was concentrated with the use of a Centricon-30 concentrator (Amicon) and stored at -80°C.
Immunoblotting
Proteins were resolved through the use of standard SDS-PAGE24 on 10% gels and transferred to a polyvinylidene difluoride Immobilon membrane (Millipore) with the use of a Mini Trans-Blot system (Bio-Rad). Membranes were blocked in a 10% NFDM-TBST solution (consisting of 10% nonfat dry milk in 0.1 mol/L Tris-HCl, 0.15 mmol/L NaCl, and 0.05% Tween-20, pH 7.5) and probed with the anti-ER monoclonal antibodies H-222, D-75 (kindly provided by Dr G. Greene, University of Chicago [Illinois]) or with 1D5 (DAKO Co). The anti–urokinase plasminogen activator receptor monoclonal antibody used as a control was from American Diagnostica Inc. For detection of reactive proteins, an enhanced chemiluminescence detection kit with anti-mouse horseradish peroxidase–linked IgG was used (ECL kit, Amersham).
Electrophoretic Mobility Shift Assay
The reactions were performed as described previously.25 Nuclear extracts (typically 5 to 10 µg of total protein) from endothelial or positive and negative control cells were preincubated for 20 minutes on ice with 2 µg of poly(dI/dC) (Pharmacia Biotech) and 1 µg of single-stranded nonspecific oligonucleotide in a reaction containing 100 mmol/L NaCl, 2 mmol/L dithiothreitol, 10% glycerol, and 25 mmol/L HEPES buffer, pH 7.4, before the addition of the radiolabeled probe. The unlabeled competitor oligonucleotides (25 ng) or either of the anti-ER antibodies 1D5 or H-222 (1 µg) was added during preincubation. Two slightly different consensus oligonucleotides with characteristic ERE palindromic motifs were used: a 19-bp oligomer, 5'-AATTCGGTCACGCTGACCA-3', or a 27-bp oligomer from the vitellogenin A2 ERE, 5'-GATCCTAGAGGTCACAGTGACCTACGA-3' (kindly provided by Dr G. Greene). The oligonucleotides were end-labeled with [
-32P]dATP through the use of T4 polynucleotide kinase, adjusted to 
30 000 cpm/0.25 ng/µL, and 1 µL/19-µL sample was added. After additional incubation for 30 minutes at room temperature, the samples were directly loaded on a prerun 4.6% polyacrylamide gel in 0.5x TBE (0.5x: 0.045 mol/L Tris/borate, 0.002 mL EDTA) and run at 10 mA for 3 hours. The gel was fixed in 10% acetic acid plus 20% methanol, vacuum dried, and exposed to x-ray film.
mRNA Analysis
Total RNA was extracted directly in the culture plates with the use of RNAzol (Biotecx Labs) from endothelial cells washed with cold PBS. The RNA was kept under ethanol at -20°C until use. Radiolabeled antisense RNA probes were synthesized (Maxiscript, Ambion Inc) from a lambda OR3 cDNA clone as a template (POR3, American Type Culture Collection) coding for a region in the DNA-binding domain of the ER,26 which was subcloned into a pBluescript II SK± (Stratagene). For Northern hybridization analysis, total RNA samples were subjected to denaturing agarose formaldehyde electrophoresis,27 transferred to membranes (Z-blot, Bio-Rad), and hybridized to the ER riboprobe for 20 hours at 63°C. The stringent wash conditions for membranes included 63°C in 0.2x SSC (1x: 0.15 mL sodium chloride, 0.015 mol/L sodium citrate) plus 0.1% SDS for 30 minutes.
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Identification of ERs in Endothelial Cell Nuclear Extracts by Immunoblotting
Protein extracts from separated nuclear and cytosolic fractions were subjected to standard SDS electrophoresis, transferred to a membrane, and probed with various antibodies against the ER. The results shown in Fig 1A
demonstrate the presence of an immunoreactive protein fraction with an apparent molecular mass of 67 kD recognized by the anti-ER antibody H-222 in nuclear extracts from BAEC (lane B) and HUVEC (lane C) that corresponds to a band in the nuclear extracts from the estrogen-responsive GH3 cells (lane A). This finding was confirmed with the use of other anti-ER monoclonal antibodies specific to different epitopes. The results shown on Fig 1B verify the presence of a D-75–immunoreactive band in nuclear extracts from HAEC that corresponds in mobility to the positive control and to the band recognized by H-222 on Fig 1A. The same pattern of immunostaining in all types of endothelial cells studied was also obtained with another anti-ER monoclonal antibody, 1D5, that is specific to the amino-terminal region of the receptor (Fig 1C). The immunostaining patterns obtained with the three antibodies were highly reproducible and did not depend on the type of antibody used. Parallel experiments with a monoclonal antibody from the same class but specific to the anti–urokinase plasminogen activator receptor (see "Methods") failed to produce a distinctive band in this region and confirmed the specificity of the 67-kD protein toward the anti-ER antibodies used. The cytosolic fractions from all cell types equally lacked any distinctive immunostained band (not shown). The presence of the ER-immunoreactive band did not change in endothelial cells cultivated up to passage 8.
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Proteins From Endothelial Cells Form Specific Complexes With the ERE
Nuclear extracts from early passage endothelial cells were probed for their ability to interact in vitro with ER consensus oligonucleotide sequences. Two complexes with considerable differences in mobility were clearly observed (Fig 2A). The complexes formed with endothelial proteins correspond in mobility and specificity to complexes formed with extracts from GH3 estrogen-responsive cells. Nuclear extracts from the ER-negative breast tumor cell line BT-20 were able to form only one complex that was unaffected by the addition of unlabeled ERE. Titration analysis with nuclear and cytosolic extracts and unlabeled specific and nonspecific oligonucleotides (Fig 2B) indicated that the two complexes are affected by the consensus ERE but not by the nonspecific oligonucleotide and therefore represent specific DNA/protein complexes. Also, these complexes are formed only with nuclear proteins, which again emphasizes their authenticity. The same pattern of specific complex formation was observed with protein extracts from transfected COS cells expressing high levels of ER (kindly provided by Dr G. Greene). The mobility and intensity of these complexes did not depend on the presence of estrogen in either the reactions or the culture medium independent of the cell type: GH3 extracts displayed the same pattern as endothelial ones. The complexes shown in Fig 2A through 2C were formed with the use of the vitellogenin A2 27-mer ERE, but similar results were obtained with the 19-mer oligomer.
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To confirm that authentic ER was a component of these complexes, electrophoretic mobility shift assays were performed in the presence of the anti-ER monoclonal antibody 1D5 (Fig 2C
). In HAEC and HUVEC, the antibody induced a nearly complete supershift of the slow moving complex, whereas in GH3 and BAEC, the shift was not total, and a certain amount of this complex remained. Furthermore, in BAEC, the shifted complex had a different mobility. The faster moving complex was affected to a lesser extent in the supershift experiments. Similar results were obtained with another ER-specific antibody, H-222. Otherwise, we did not find any cell type or species specificity of the complexes: human arterial, human umbilical vein, and bovine endothelial nuclear extracts were equally able to form specific complexes and showed identical affinity toward each of the EREs used.
Endothelial Cells Express a Full-Length mRNA for the ER
In these experiments, total RNA was extracted from early passage cell cultures and analyzed through Northern blot analysis with an 0.4-kb antisense RNA spanning the region between nucleotides 1170 and 1600 of the ER cDNA (see "Methods"). The results shown in Fig 3 demonstrate the presence of abundant mRNA for the ER with the expected 6.2-kb length in all endothelial cell types studied. The presence of ER mRNA in endothelial cells was also verified through RNase protection assays with the same radiolabeled probe. RNA extracts from endothelial cells were able to protect the 0.4-kb antisense ER RNA from degradation by RNases A and T1 (data not shown). We did not find any site- or species-specific differences with regard to the level or size of ER mRNA from endothelial cells. Furthermore, this message did not appear to be affected by the treatment of cells with estrogen, which is known to modulate the expression of ER mRNA in breast tumor cells.28
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Discussion |
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The concept that ovarian hormones may influence the endothelial functions in various physiological and pathophysiological conditions is not new.20 Data continue to accumulate pointing to a positive correlation between estrogen plasma levels and fibrinolysis,29 estrogen modulation of the biosynthesis of endothelium-derived vasodilators,13 14 and enhancement by estrogen of endothelial cell activities that are important in neovascularization.30 Still, the mechanism or mechanisms of these effects have not been adequately explained. Since the effect of estrogen is realized in most cases through its intracellular receptor, attempts have been made to detect ER in vascular tissues, and it has been positively identified in vascular smooth muscle cells.19 Although previous studies have suggested the presence of ER in endothelial cells,20 21 a definitive characterization of endothelial ER has not been published, and its expression in endothelial cells has been disputed.22
With a panel of anti-ER antibodies specific for different regions of the receptor, we were able to establish the presence of a 67-kD protein in nuclear extracts of HAEC, HUVEC, and BAEC. The nuclear localization of the receptor found in endothelial cells is in agreement with the existing data for other cell types, which point to nuclear localization of ER even without ligand binding.31 32 The three monoclonal antibodies used in this study recognize distinct epitopes in the ER molecule: near the hormone-binding region of the ER (H-222),33 the "hinge" region between the hormone- and DNA-binding domains (D-75),33 and the amino-terminal domain (A/B region) of the ER (1D5).34 The fact that all three highly specific antibodies recognize the same protein fraction in all endothelial extracts confirms its authenticity and suggests that this protein may have the capacity to function as a bona fide ER.
The high affinity of ER binding to ERE has been exploited in electrophoretic mobility shift assays for studies of the mechanisms of estrogen-activated transcriptional regulation.35 36 37 Using this technique, we were able to obtain evidence that the 67-kD nuclear protein recognized by anti-ER antibodies in endothelial cell extracts can bind radiolabeled ERE with high affinity, as expected for classic ERs. The two complexes formed with ERE and nuclear extracts display different affinities: a 100-molar excess of unlabeled specific oligonucleotide completely abolished the slower moving complex, whereas the faster moving one was considerably, but not completely, reduced. Since a 100-molar excess of nonspecific oligonucleotide did not affect its intensity, it is unlikely that the latter represents nonspecific interactions. In the supershift experiments, the faster migrating complex was only marginally affected by the anti-ER antibody. One possible explanation for this divergent pattern is that the two complexes differ in the composition of additional nuclear proteins, which may account for different conformations and, therefore, different affinities toward ERE. It has been suggested that the multiple ER/ERE complexes reported in other studies were caused by different conformations38 arising probably from diversity in ER-associated nuclear proteins.37 This could also explain the cell type– and species-specific differences in the pattern of complexes formed in the presence of anti-ER antibody observed in our experiments. ER is reported to form complexes with other proteins before binding with estrogen39 or when in complex with ERE,40 41 and it is hypothesized that the number and mobility of such complexes are tissue specific. Indeed, specific control of gene transcription requiring the participation of multiple tissue-specific DNA-binding proteins has been reported,42 and a steroid hormone receptor coactivator protein has been described.43
Two similar (but not identical) EREs were used in these studies to confirm specificity of the complexes regardless of the source of the nuclear extracts. The use of different ERE consensus oligomers in the electrophoretic mobility shift assay studies did not influence the pattern of complex formation, although the 27-mer vitellogenin A2 oligonucleotide yielded consistently better autoradiographic patterns. The finding that estrogen treatment was not a requirement for the formation of specific complexes between ERE and endothelial proteins or even with proteins from the positive control cells was not surprising. Estrogen regulates the expression of target genes by binding to its receptor, which in turn is thought to dimerize, bind to EREs, and activate consensus DNA sequences. However, a distinction should be made between in vitro and in vivo situations, and there is growing evidence that estrogen is not required for specific DNA binding in vitro.35 36 37 44 45 On the other hand, ER-induced alterations in chromatin structure and trans-activation in vivo are reported to be completely dependent on the presence of estradiol.46 It has been suggested recently that the in vivo ER is bound to target DNA sequences regardless of the hormonal status of the cell but that steroid binding is required for interaction of the receptor with nuclear proteins and activation of the transcriptional machinery.47
The comparatively high amount of ER mRNA in endothelial cells observed by Northern hybridization analysis was confirmed through RNase protection assays and reflected at the protein level by immunoblot studies. Taken together, these data suggest that endothelial cells express ER at a high constitutive rate. Based on the results of immunoblotting and electrophoretic mobility shift assay experiments, this receptor is localized only in the nucleus. It also appears to be authentic and identical to the classic one described in human estrogen-responsive cells.26 However, it does not seem to be regulated in the same way as in breast cancer cells since ER mRNA level was not changed by treatment of endothelial cells with estrogen, which is known to downregulate ER expression.33
The finding of the ER in both human and bovine endothelial cells suggests conservation of estrogen responsiveness in endothelium and attests to the importance of this kind of regulation. The next step in these studies will involve a systematic characterization of the genes regulated by estrogen in endothelial cells. Several candidate genes have been identified. Estrogen is known to influence the expression of plasminogen activators tissue-type plasminogen activator and urokinase plasminogen activator and their major inhibitor, plasminogen activator inhibitor type 1, in endometrial cells.48 Furthermore, estrogen stimulates the secretion of plasminogen activators by mammary tumor cells49 50 and tissue-type plasminogen activator–producing melanoma cells.51 Estrogen administration in ovariectomized rats modulates aortic gene expression of angiotensinogen,52 which may be expressed in endothelial cells.53 Putative EREs have been described in the upstream regulatory regions of several genes of the mammalian fibrinolytic system,22 and it is possible that estrogen can directly or indirectly influence vascular fibrinolytic balance. Recently, estrogenic modulation of the biosynthesis of endothelium-derived relaxation factor (NO) in endothelial cells was reported,13 and both pregnancy and estradiol treatment increase the levels of mRNA for the calcium-dependent eNOS in the guinea pig.54 Estrogen has also been shown to modulate the expression of mRNA for intercellular adhesion proteins, E-selectin, intercellular adhesion molecule type 1, and vascular cell adhesion molecule type 155 and thus prevent monocyte adhesion during atherogenesis. Estrogen therapy has been reported to prevent retention and oxidation of lipids, to accelerate the metabolism of LDL, and to decrease cholesterol levels in blood. A summary of endothelial genes identified as candidates for estrogen regulation in vascular endothelial cells is presented in the Table. The presence of an immunoreactive and ERE-specific estrogen receptor in vascular endothelial cells, together with the finding of DNA sequences similar to EREs in the regulatory regions of several endothelial genes, argues for a role of estrogen in transcriptional regulation of endothelium.
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On the other hand, estrogen may participate in transcriptional regulation of genes lacking consensus EREs via interactions with other DNA response elements. Thus, a half-palindromic ERE may compose part of a phorbol ester–responsive element, which in turn differs in only one nucleotide from a canonical transcription factor AP-1 recognition site.40 Indeed, ER-mediated activation of different genes involving Fos/Jun complexes has been described,40 56 and conversely, the regulation of c-fos gene expression through ER has been suggested.57 In addition, estrogen activates the binding of a nuclear factor-
B enhancer–specific protein to its consensus DNA site in uterine tissue.58 The recently reported serum-induced activation of ER in vascular smooth muscle cells59 and estrogen-stimulated tyrosine kinase activation in cultured aortic endothelial cells60 support the concept of cross-talk between mitogen- and steroid hormone–signaling pathways in vascular tissue. These and other data61 62 indicate a convergence of hormonal induction and activation of transduction pathways at the transcriptional level and suggest alternative mechanisms of estrogen action on endothelium.
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Acknowledgments |
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This work was supported by National Institutes of Health grant HL-50878 and by a Merit Award from the Department of Veterans Affairs Research Service. Dr Vaughan is the recipient of a Clinical Investigator Award from the Department of Veterans Affairs Research Service. We are grateful to Dr Fritz Parl (Vanderbilt University Medical Center) for his contribution to the study and critical review of the manuscript. We greatly appreciate the help of Dr Geoffrey Greene (University of Chicago [Illinois]) in providing some of the antibodies, ER-containing protein extracts, and sequence for vitellogenin A2 ERE used in the study. The generous gift of ICI 164,384 by Dr A.E. Wakeling (Zeneca Pharmaceuticals, UK) is gratefully acknowledged. We also acknowledge the helpful discussions with Drs Allen Naftilan and Mary A. Brown.
Received December 18, 1995; revision received January 31, 1996; accepted February 1, 1996.
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 N. J. Alkayed, I. Harukuni, A. S. Kimes, E. D. London, R. J. Traystman, P. D. Hurn, and P. A. Grady Gender-Linked Brain Injury in Experimental Stroke • Editorial Comment Stroke, January 1, 1998; 29(1): 159 - 166. [Abstract] [Full Text] [PDF]
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K. Sudhir, T. M. Chou, K. Chatterjee, E. P. Smith, T. C. Williams, J. P. Kane, M. J. Malloy, K. S. Korach, and G. M. Rubanyi Premature Coronary Artery Disease Associated With a Disruptive Mutation in the Estrogen Receptor Gene in a Man Circulation, November 18, 1997; 96(10): 3774 - 3777. [Abstract] [Full Text]
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V. Guetta, A. A. Quyyumi, A. Prasad, J. A. Panza, M. Waclawiw, and R. O. Cannon III The Role of Nitric Oxide in Coronary Vascular Effects of Estrogen in Postmenopausal Women Circulation, November 4, 1997; 96(9): 2795 - 2801. [Abstract] [Full Text]
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G. M.C. Rosano, A. M. Caixeta, S. Chierchia, S. Arie, M. Lopez-Hidalgo, W. I. Pereira, F. Leonardo, C. M. Webb, F. Pileggi, and P. Collins Short-term Anti-Ischemic Effect of 17ß-Estradiol in Postmenopausal Women With Coronary Artery Disease Circulation, November 4, 1997; 96(9): 2837 - 2841. [Abstract] [Full Text]
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V. L. Baker, V. A. Chao, J. T. Murai, C. J. Zaloudek, and R. N. Taylor Human Umbilical Vessels and Cultured Umbilical Vein Endothelial and Smooth Muscle Cells Lack Detectable Protein and mRNA Endocing Estrogen Receptors Reproductive Sciences, November 1, 1997; 4(6): 316 - 324. [Abstract] [PDF]
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Y. Matsubara, M. Murata, K. Kawano, T. Zama, N. Aoki, H. Yoshino, G. Watanabe, K. Ishikawa, and Y. Ikeda Genotype Distribution of Estrogen Receptor Polymorphisms in Men and Postmenopausal Women From Healthy and Coronary Populations and Its Relation to Serum Lipid Levels Arterioscler. Thromb. Vasc. Biol., November 1, 1997; 17(11): 3006 - 3012. [Abstract] [Full Text]
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K. Krasinski, I. Spyridopoulos, T. Asahara, R. van der Zee, J. M. Isner, and D. W. Losordo Estradiol Accelerates Functional Endothelial Recovery After Arterial Injury Circulation, April 1, 1997; 95(7): 1768 - 1772. [Abstract] [Full Text]
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I. Spyridopoulos, A. B. Sullivan, M. Kearney, J. M. Isner, and D. W. Losordo Estrogen-Receptor–Mediated Inhibition of Human Endothelial Cell Apoptosis : Estradiol as a Survival Factor Circulation, March 18, 1997; 95(6): 1505 - 1514. [Abstract] [Full Text]
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