JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2000; 36:1972-1978
© 2000 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chandrasekar, B.
Right arrow Articles by Tanguay, J.-F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chandrasekar, B.
Right arrow Articles by Tanguay, J.-F.

EXPERIMENTAL STUDY

Local delivery of 17-beta-estradiol decreases neointimal hyperplasia after coronary angioplasty in a porcine model

Baskaran Chandrasekar, MDa and Jean-François Tanguay, MDa

a Department of Medicine, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada

Manuscript received October 26, 1999; revised manuscript received May 17, 2000, accepted July 12, 2000.

Reprint requests and correspondence: Dr. Jean-François Tanguay, Montreal Heart Institute, Research Center, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
tanguay{at}icm.umontreal.ca


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
BACKGROUND

Neointimal hyperplasia is an important mechanism of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Systemically administered estrogen is known to inhibit neointimal formation after arterial injury.

OBJECTIVES

We sought to assess the efficacy of locally delivered 17-beta-estradiol (BE) in inhibiting neointimal hyperplasia after PTCA.

METHODS

Eighteen juvenile farm pigs were studied. Coronary angioplasty was performed in all three coronary arteries of each animal. After PTCA, each coronary artery in each pig was randomized to receive either local delivery of 600 µg BE, vehicle alone or PTCA only. Twelve animals were euthanized at 28 days for morphometric analysis, and four animals were euthanized at seven days for immunohistochemical analysis of vascular smooth muscle cell (SMC) proliferative activity. Two animals died a few days after PTCA and were excluded.

RESULTS

On morphometric study, the arterial segments treated with BE demonstrated significantly less neointimal proliferation. Arteries treated with BE had reductions in several indexes of restenosis compared with arteries treated with vehicle alone or PTCA only: neointimal area (0.4 ± 0.09 mm2 for BE vs. 1.14 ± 0.33 mm2 for vehicle alone vs. 0.88 ± 0.2 mm2 for PTCA only, p < 0.05), percent neointima (12.16 ± 2.57% vs. 25.46 ± 4.73% vs. 23.02 ± 3.97%, p < 0.025), neointima/media area (0.59 ± 0.14 vs. 1.75 ± 0.41 vs. 1.67 ± 0.43, p < 0.01) and restenotic index (1.3 ± 0.14 vs. 2.42 ± 0.22 vs. 2.4 ± 0.23, p < 0.005). Immunohistochemistry showed decreased SMC proliferative activity in BE-treated arteries compared with the other two treatment groups (p < 0.05).

CONCLUSIONS

Local delivery of BE significantly decreases neointimal hyperplasia after PTCA in pigs, probably by the inhibition of SMC proliferation.

Abbreviations and Acronyms
  BE = 17-beta-estradiol
  EEL = external elastic lamina
  FL = fracture length
  HPCD = 2-hydroxypropyl-beta-cyclodextrin
  IEL = internal elastic lamina
  PCNA = proliferating cell nuclear antigen
  PTCA = percutaneous transluminal coronary angioplasty
  SMC = smooth muscle cell

Restenosis is currently the major limitation of percutaneous transluminal coronary angioplasty (PTCA), as seen in up to 30% to 40% of patients. Neointimal proliferation is a fundamental mechanism of restenosis. Although brachytherapy has been reported to show beneficial effects (1,2), no effective therapy exists yet for neointimal proliferation. Vascular smooth muscle cell (SMC) migration and proliferation occur as early as 36 h after arterial injury (3). In cell culture assays, 17-beta-estradiol (BE) inhibited the migration and proliferation of rat vascular SMCs (4,5). Similar effects have also been shown with human vascular SMCs from the saphenous vein (6). Prolonged systemic administration of estrogen has been shown to inhibit intimal hyperplasia in animal studies (7,8). In the present experiment, we tested the hypothesis that local administration of BE during PTCA could effectively inhibit neointimal proliferation.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Animal preparation.   Eighteen juvenile farm pigs (nine sexually immature females with intact ovaries and nine castrated males), approximately three months old and weighing 20 to 25 kg, were studied. The males were castrated at birth. The animals were fed regular pig chow in which the bulk of protein was derived from a nonsoybean source, as soybean contains significant amounts of phytoestrogens, which could potentially influence the effect of BE. The study was approved by and conducted in accordance with the guidelines of the Animal Care and Ethical Research Committee of the Montreal Heart Institute. Before the procedure, animals were given 650 mg of acetylsalicylic acid and 30 mg of nifedipine orally, premedicated with an intramuscular injection of 6 mg/kg body weight of a mixture of tiletamine hydrochloride and zolazepam hydrochloride and given 0.5 mg of atropine. The invasive procedure was performed under general anesthesia with a mixture of isoflurane (1% to 1.5%) and oxygen-enriched air. The right femoral artery was cannulated percutaneously, and an 8F arterial sheath was introduced. After arterial access had been obtained, 100 mg of lidocaine and 250 U/kg of heparin were administered intra-arterially through the sheath. The activated coagulation time was maintained at >300 s throughout the procedure.

Angioplasty and local delivery.   Standard PTCA equipment was used. An 8F right Amplatz guiding catheter and right Judkin’s guiding catheter were used for cannulation of the left and right coronary arteries, respectively. Heart rate, blood pressure and the electrocardiogram were monitored throughout the experiment. Coronary angioplasty was performed with a balloon size chosen to correspond to a balloon/artery ratio of 1.1:1.2. Three 30-s inflations at 10 atm were performed with a 30-s interval between inflations. All three coronary arteries of each animal were subjected to PTCA. After PTCA, each animal’s coronary artery was randomized to receive either 600 µg BE locally, vehicle alone locally or PTCA only. The chemicals BE and its vehicle 2-hydroxypropyl-beta-cyclodextrin (HPCD) were purchased from Sigma Chemicals. The InfusaSleeve catheter (LocalMed, Inc., Palo Alto, California) was used for local delivery (9). Five milliliters of the designated substance was delivered at a driving pressure of 10 atm and support balloon pressure of 6 atm. The dose of BE (~30 µg/kg body weight) was chosen as representative of a daily dose of systemic BE therapy used in previous studies, which ranges from 10 to 100 µg/kg.

Of the 18 animals, two died a few days after PTCA and were excluded; thus, 16 animals were analyzed. Twelve animals were euthanized at 28 days and four at 7 days. After premedication and anesthesia, the right internal jugular vein and common carotid artery were cannulated. After cross-clamping of the descending thoracic aorta through a left lateral thoracotomy, exsanguination was performed, with simultaneous administration of 1 liter of 0.9% sodium chloride solution. The heart was perfusion-fixed in vivo with 2 liter of 10% buffered formalin at 200 mm Hg, removed from the animal and placed in 10% buffered formalin solution. The site of PTCA was identified in relation to adjacent side branches, which served as landmarks. The injured segment was harvested with a 1-cm normal segment proximal and distal to the injured site. Serial sections 3 to 5 mm long were made from the harvested segment, with a minimum of at least three sections (maximum of 5) from each PTCA site. The sections were stored in buffered 10% formalin and dehydrated with increasing concentrations of alcohol, followed by treatment with xylene and paraffin. Each section was cut into 6-µm-thick slices with a microtome (Olympus cut 4060 E) and stained with Verhoeff’s stain for morphometric analysis.

Morphometric analysis.   Measurements were made with a video microscope linked to a 486 personal computer and customized software. A minimum of three sections for each injured segment were analyzed, and the results were averaged. When individual values were widely discrepant for an injured segment (observed in only one injured vessel), all sections demonstrating rupture of the internal elastic lamina (IEL) were included for analysis. Analyses were performed by an examiner who had no knowledge of the treatment assignment of the injured segments. The areas of external elastic lamina (EEL), IEL and lumen were measured by digital planimetry; neointimal area (IEL – lumen area) and medial area (EEL – IEL area) were obtained. The fracture length (FL) was measured as the length of discontinuity of the injured IEL, and measurement of the extent of injury was controlled by standardization for each artery, expressed in relation to the circumference of the IEL (10,11). The extent of injury was determined by the ratio of FL to IEL circumference (FL/IEL). The percent neointima was defined as the percent total vessel area occupied by the neointima ([intimal area/EEL] x 100). Morphologic percent stenosis was calculated as 100 (1 – lumen/IEL area) (10). The restenotic index was defined as [intimal area/(intimal area + medial area)]/(FL/IEL circumference) (11). Injury score was determined as previously defined (12).

Immunohistochemistry.   After slicing with a microtome and blocking of nonspecific antibodies, the sections were treated with mouse anti–proliferating cell nuclear antigen (PCNA) antibodies and diluted biotinylated goat antimouse antibodies. They were incubated with avidin-biotin (Elite ABC Kit, Vector Laboratories, Burlingame, California), developed with 3,3'-diaminobenzidine (Vector Laboratories) and counterstained with hematoxylin. Porcine liver cells served as the positive control. For each section, a 6-µm slice counterstained with hematoxylin without treatment with the primary antibody (mouse anti-PCNA) served as the negative control.

Immunohistochemistry was performed on samples from animals euthanized at seven days. The percentage of proliferating SMCs was obtained by dividing the number of PCNA-positive SMCs by the total number of SMCs in each field; separate measurements were made for neointimal and medial layers. To standardize comparison among treatment groups, measurements were obtained at four fixed locations separated by 90° for each section, and the results were averaged. For each segment, two sections demonstrating a maximal neointimal response were analyzed, and the results averaged.

Statistical analysis.   Values are expressed as the mean value ± SEM. Kruskal-Wallis analysis was used for comparison of data among the three groups. Multiple comparisons between the BE and PTCA-only groups and between the vehicle-only and PTCA-only groups were made using the Student-Newman-Keuls test. Chi-square analysis was used for comparison of proportions. Values were considered significant at p < 0.05.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
After PTCA and local delivery, the animals were allowed to recover and gained weight steadily. Two animals died 48 and 72 h, respectively, after the procedure and were excluded; thus, 16 animals were studied. Autopsy of the two animals revealed occlusive thrombus at the site of PTCA (in the BE-treated vessel in one pig and in the vessel treated with PTCA only in the other pig).

No changes in heart rate, electrocardiographic variables or blood pressure were observed during local delivery.

Injured segments.   The balloon/artery ratio and artery diameter were similar among the three treatment groups (Table 1). Segments with intact IEL in which discernible injury was absent were excluded from analysis (two from the PTCA-only group and one from the vehicle-only group). Two segments were lost during harvesting (one from the vehicle-only group and one from the PTCA-only group).


View this table:
[in this window]
[in a new window]
  		Table 1 Morphometric Analysis

 
Morphometric analysis.   On morphometric analysis at 28 days, arterial segments treated with local delivery of BE showed significantly less neointimal hyperplasia compared with the other two treatment groups (Fig. 1). This beneficial effect was noted in all of the variables of neointimal response to injury analyzed (Table 1). The extent of injury was similar among the three groups, suggesting that the use of the InfusaSleeve catheter was not associated with enhanced risk of injury. The noninjured segments proximal and distal to the sites of PTCA appeared morphologically normal, with no evidence of inflammation or necrosis.



View larger version (32K):
[in this window]
[in a new window]
  		Figure 1 Representative light micrographs (x40) of arterial segments from the three treatment groups: (A) BE-treated artery (extent of injury = 0.23, neointimal area = 0.24 mm2); (B) PTCA only–treated artery (extent of injury = 0.29, neointimal area = 1.00 mm2); and (C) vehicle only–treated artery (extent of injury = 0.23, neointimal area = 1.3 mm2).

 
To exclude the existence of an inhibitory effect on intimal proliferation due to the vehicle, analyses were performed comparing segments treated with vehicle alone and PTCA only, which showed no significant differences. In contrast, significantly less intimal hyperplasia was observed in BE-treated segments as compared with segments treated with PTCA only (Fig. 2). Compared with PTCA only or vehicle alone, BE decreased neointimal formation by ~50%.



View larger version (23K):
[in this window]
[in a new window]
  		Figure 2 Comparison of (A) neointimal area (NI); (B) neointimal/media area (NI/M); (C) restenotic index; and (D) neointimal area/fracture length (NI/F) between PTCA-only and BE-treated groups, and between PTCA only and vehicle-only groups. *p = NS. **p < 0.05.

 
The existence of a significant protective effect of BE as compared with placebo or vehicle treatment by gender was then assessed (Table 2 and 3). Although the extent of injury in the BE-treated segments appeared slightly greater in males and slightly less in females, compared with the other two treatment groups, they were not statistically significant. A significant protective effect of BE on the neointimal response to injury was demonstrated in both genders.


View this table:
[in this window]
[in a new window]
  		Table 2 Morphometric Data in Male Pigs

 

View this table:
[in this window]
[in a new window]
  		Table 3 Morphometric Data in Female Pigs

 
There were no significant differences in the effect of BE in the different arteries treated (left anterior descending vs. circumflex vs. right coronary artery). Neointimal area (0.28 ± 0.16 vs. 0.47 ± 0.16 vs. 0.46 ± 0.15 mm2, p = NS), neointimal area/FL (0.17 ± 0.04 vs. 0.35 ± 0.11 vs. 0.25 ± 0.06, p = NS) and restenotic index (1.2 ± 0.14 vs. 1.72 ± 0.27 vs. 1.12 ± 0.25, p = NS) were similar in the different arteries treated with BE.

Immunohistochemistry.   A statistically significant decrease in proliferating SMCs (PCNA-positive SMCs) was seen in the arterial segments treated with BE. Among the different groups, the percentage of PCNA-positive SMCs in the neointima were 0.43 ± 0.26% with BE, 4.26 ± 1.17% with PTCA only and 4.27 ± 1.37% with vehicle alone (p < 0.05 for BE vs. other two groups). There were no significant differences in the percentage of PCNA-positive SMCs in the media between the three groups: 0.4 ± 0.15%, 1.38 ± 0.87% and 1.24 ± 0.79% for BE, PTCA only and vehicle alone, respectively (p = NS).

Vascular remodeling.   To determine the effect on vascular remodeling of the agents used, the EEL areas of the injured segment and of the normal vessel proximal to the PTCA site were obtained, and their ratio calculated (10). No significant difference between the groups was noted: 1.01 ± 0.05, 1.16 ± 0.11 and 1.31 ± 0.15, respectively, for BE, PTCA only and vehicle alone (p = NS).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The present study demonstrates, for the first time, to our knowledge, that locally delivered BE decreases neointimal proliferation after PTCA in pigs. The study also shows that local delivery of BE can be performed safely using the InfusaSleeve catheter, without significant additional injury.

Local delivery and injury response.   Systemic administration of pharmacologic agents may not achieve a local concentration of the agent to produce a significant effect; in addition, higher doses may result in intolerance or toxicity. Unlike systemic administration, local delivery involves the delivery of a single dose of the agent during PTCA. Therefore, local delivery appears to be a potentially effective method for the prevention of tissue response to injury. Several agents have shown beneficial results in reducing neointimal proliferation after PTCA in animal experiments. Locally delivered ethanol (13), nitric oxide (10), vascular endothelial growth factor (14) and antisense oligonucleotides (15) have resulted in decreased neointimal proliferation after arterial injury. Two clinical trials have demonstrated that local radiation therapy may have the potential to reduce restenosis after PTCA (1,2).

17-Beta-estradiol and injury response.   Previous experiments in animals have demonstrated that estrogen administered subcutaneously for up to three weeks inhibited the myointimal response to arterial injury (7,8). Recently, a preliminary report has suggested that short-term subcutaneous estrogen therapy (6 to 17 days) may be effective in reducing the injury response (16). Estrogen administered intramuscularly for at least three weeks has also demonstrated the potential to inhibit vascular SMC proliferation and neointimal hyperplasia (17). However, the efficacy of local delivery of BE to inhibit intimal hyperplasia has not been previously studied.

In the present study, local delivery of BE was associated with a markedly lower proliferative response compared with the other two treatment groups. The neointimal area, neointima/media area ratio, restenotic index and morphologic percent stenosis were all significantly lower in the BE-treated arterial segments. The decreased neointimal hyperplasia after treatment with BE is probably due to the inhibition of SMC proliferation. Assessment at different time points could possibly provide additional information on the effect of BE on SMC proliferation. Studies examining SMC proliferation after arterial injury have shown that maximal SMC proliferative activity occurs during the first seven days after experimental arterial injury and rapidly decreases beyond seven days (18). We were able to demonstrate significantly lower SMC proliferation at seven days in the arterial segments treated with BE, compared with the PTCA-only and vehicle-only treatment groups. The inhibitory effect of BE on SMC proliferation may be due to a direct effect on SMC proliferation (19) or to enhanced synthesis of nitric oxide by BE (20,21). Nitric oxide is known to inhibit both SMC migration (22) and proliferation (23). The biologic effects of estrogen, like other steroid hormones, involve intracellular receptors (24). Estrogen receptors have been demonstrated in coronary arteries obtained from autopsy specimens in both premenopausal and postmenopausal women (25) and in cell cultures of human saphenous vein and internal mammary artery specimens (26). The beneficial effects of BE—the predominant circulating estrogen in premenopausal women—on vascular injury response may not be replicated by other kinds of estrogens. For example, conjugated equine estrogen was found to have no effect on neointimal proliferation in nonhuman atherosclerotic primate models (27). In this study, it is unlikely that loss of estrogen receptors in the hypercholesterolemic monkeys could be responsible for the lack of response to conjugated equine estrogen on neointimal proliferation, as conjugated equine estrogen treatment did result in a statistically significant decrease in atherosclerotic plaque area and inhibited the progression of atherosclerosis (with no effect on neointimal proliferation) in the same monkeys, thereby demonstrating responsiveness to estrogen. Simultaneous administration of progesterone may attenuate the vascular injury response to BE (28). A sexually dimorphic response to estrogen has been reported after arterial injury, with intact male rats deriving no benefit from estrogen therapy (29). However, this sexually dimorphic effect was not observed in another experiment with gonadectomized rats (8). In the present study, a significant effect of BE on the neointimal proliferative response was noted in both genders, although the male animals used in the study had been castrated at birth.

Vehicle.   17-Beta-estradiol is a lipophilic compound with poor solubility in aqueous solutions; therefore, it needs a vehicle for parenteral administration. 2-Hydroxypropyl-beta-cyclodextrin, a starch derivative, has been successfully tested as an effective excipient for protein drugs (30). The pharmacokinetics of HPCD are similar to that of insulin, and the toxic dose (nephrotoxicity) has been estimated to be 200 mg/kg in rats (31). The dose of HPCD used to dissolve BE in the present study was 0.63 mg/kg, far below the toxic dose. Furthermore, HPCD has been used for administration of ophthalmic preparations and intravenous anesthetic agents in humans (32,33). In the present study, the neointimal response to injury was similar in HPCD-treated arteries and arteries undergoing PTCA only. Therefore, HPCD itself did not exert any significant influence on neointimal proliferation.

Clinical evidence.   Retrospective studies in humans have shown no benefit of hormonal replacement therapy on angiographic restenosis after PTCA (34), although one study did show a beneficial effect after directional atherectomy (35). However, conjugated estrogen (and not BE) was the predominant form of estrogen used in many of these patients, and no information on concomitant use of progesterone is available. In addition, it is not known whether hormone replacement therapy could achieve a sufficient concentration of estrogen locally at the PTCA site to exert a significant response.

Study limitations.   It is possible that spillover of BE into the systemic circulation could occur during local delivery. Also, tissue uptake and retention of BE after local delivery were not measured. However, the results of the morphometric and immunohistochemical analyses clearly demonstrate a significant difference in the arteries treated with BE compared with untreated vessels, which is highly suggestive of an effect due to the locally delivered BE. The efficacy of the InfusaSleeve catheter in delivering various agents intramurally has been reported in previous studies. At a support balloon pressure similar to that used in the present study, a sixfold higher concentration in the arterial wall was achieved by local delivery, as compared with the arterial wall concentration achieved by systemic administration (36). In another study, persistent retention in the arterial wall of locally delivered tissue factor pathway inhibitor was demonstrated for at least 48 h after delivery (37). A strong argument against a systemic effect due to spillover is that, in the present model, where all three treatment arms were applied in each animal, the systemic effects of BE (if any) due to spillover would be expected to affect all three coronary arteries in each animal equally, providing equal protection to all vessels. The differences in the results between the arteries treated with BE compared with PTCA only and vehicle alone cannot therefore be attributed to such systemic effects. Furthermore, BE that enters the circulation is rapidly eliminated, mostly by the liver (38).

Conclusions.   We have shown that a single dose of BE delivered locally during PTCA in a porcine model has the potential to decrease neointimal hyperplasia significantly, probably by inhibition of SMC proliferation. Previous studies have demonstrated that treatment with BE is associated with inhibition of proliferation of human vascular SMCs in cell culture assays (6). The local delivery of BE can be performed safely with the InfusaSleeve catheter, without risk of additional injury. The local administration of BE is therefore a promising new approach that may be useful in preventing the proliferative response after PTCA. Its usefulness in preventing restenosis after PTCA merits further investigation.


   Acknowledgments
 
The authors are indebted to Pascale Geoffroy, MSc, and Julie Lebel for assistance in the laboratory; to Martin G. Sirois, PhD, Dominique Lauzier and Veronique Philibert for assistance with immunohistochemistry and morphometry; and to Stanley Nattel, MD, FACC, for his valuable suggestions in the manuscript preparation.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med. 1997;336:1697–1703[Abstract/Free Full Text]
  2. King SB III, Williams DO, Chougule P, et al. Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty: results of the Beta Energy Restenosis Trial (BERT). Circulation. 1998;97:2025–2030[Abstract/Free Full Text]
  3. Clowes AW, Reidy MA, Clowes MM. Kinetics of cellular proliferation after arterial injury: smooth muscle cell growth in the absence of endothelium. Lab Invest. 1983;49:327–333[Medline]
  4. Akishita M, Ouchi Y, Miyoshi H, et al. Estrogen inhibits cuff-induced intimal thickening of rat femoral artery: effects on migration and proliferation of vascular smooth muscle cells. Atherosclerosis. 1997;130:1–10[CrossRef][Medline]
  5. Kolodgie FD, Jacob A, Wilson PS, et al. Estradiol attenuates directed migration of vascular smooth muscle cells in vitro. Am J Pathol. 1996;148:969–976[Abstract]
  6. Dai-Do D, Espinosa E, Liu G, et al. 17-Beta-estradiol inhibits proliferation and migration of human vascular smooth muscle cells: similar effects in cells from postmenopausal females and in males. Cardiovasc Res. 1996;32:980–985[CrossRef][Medline]
  7. Sullivan TR Jr, Karas RH, Aronovitz M, et al. Estrogen inhibits the response to injury in a mouse carotid artery model. J Clin Invest. 1995;96:2482–2488[Medline]
  8. Chen SJ, Li H, Durand J, Oparil S, Chen YF. Estrogen reduces myointimal proliferation after balloon injury of rat carotid artery. Circulation. 1996;93:577–584[Abstract/Free Full Text]
  9. Moura A, Lam JYT, Hebert D, et al. Intramural delivery of agent via a novel drug-delivery sleeve: histological and functional evaluation. Circulation. 1995;92:2299–2305[Abstract/Free Full Text]
  10. Varenne O, Pislaru S, Gillijns H, et al. Local adenovirus-mediated transfer of human endothelial nitric oxide synthase reduces luminal narrowing after coronary angioplasty in pigs. Circulation. 1998;98:916–926
  11. Bonan R, Paiement P, Scortichini D, Cloutier MJ, Leung TK. Coronary restenosis: evaluation of a restenosis injury index in a swine model. Am Heart J. 1993;126:1334–1340[CrossRef][Medline]
  12. Karas SP, Gravanis MB, Santoian EC, Robinson KA, Anderberg KA, King SB III. Coronary intimal proliferation after balloon injury and stenting in swine: an animal model of restenosis. J Am Coll Cardiol. 1992;20:467–474[Abstract]
  13. Liu MW, Anderson PG, Luo JF, Roubin GS. Local delivery of ethanol inhibits intimal hyperplasia in pig coronary arteries after balloon injury. Circulation. 1997;96:2295–2301[Abstract/Free Full Text]
  14. Asahara T, Bauters C, Pastore C, et al. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation. 1995;91:2793–2801[Abstract/Free Full Text]
  15. Sirois MG, Simons M, Edelman ER. Antisense oligonucleotide inhibition of PDGFR-beta receptor subunit expression directs suppression of intimal thickening. Circulation. 1997;95:669–676[Abstract/Free Full Text]
  16. Mori T, Durand J, Chen YF, Thompson JA, Oparil S. Short-term estrogen treatment prior to and following balloon injury of rat carotid artery effectively blunts the vascular injury response. (abstr)J Am Coll Cardiol. 1999;33(Suppl):259A
  17. Foegh ML, Asotra S, Howell MH, Ramwell PW. Estradiol inhibition of arterial neointimal hyperplasia after balloon injury. J Vasc Surg. 1994;19:722–726[Medline]
  18. Hanke H, Strohschneider T, Oberhoff M, Betz E, Karsch KR. Time course of smooth muscle cell proliferation in the intima and media of arteries following experimental angioplasty. Circ Res. 1990;67:651–659[Abstract/Free Full Text]
  19. Mendelsohn ME, Karas RH. Estrogen and the blood vessel wall. Curr Opin Cardiol. 1994;9:619–626[Medline]
  20. Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T. Up-regulation of nitric oxide synthase by estradiol in human aortic endothelial cells. FEBS Lett. 1995;360:291–293[CrossRef][Medline]
  21. Hayashi T, Yamada K, Esaki T, et al. Estrogen increases endothelial nitric oxide by a receptor-mediated system. Biochem Biophys Res Commun. 1995;214:847–855[CrossRef][Medline]
  22. Sarkar R, Meinberg EG, Stanley JC, Gordon D, Webb RC. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells. Circ Res. 1996;78:225–230[Abstract/Free Full Text]
  23. Cornwell TL, Arnold E, Boerth NJ, Lincoln TM. Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP. Am J Physiol. 1994;267:C1405–C1413[Medline]
  24. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999;340:1801–1811[Free Full Text]
  25. Losordo DW, Kearney M, Kim EA, Jekanowski J, Isner JM. Variable expression of the estrogen receptor in normal and atherosclerotic coronary arteries of premenopausal women. Circulation. 1994;89:1501–1510[Abstract/Free Full Text]
  26. Karas RH, Patterson BL, Mendelsohn ME. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation. 1994;89:1943–1950[Abstract/Free Full Text]
  27. Geary RL, Adams MR, Benjamin ME, Williams JK. Conjugated equine estrogens inhibit progression of atherosclerosis but have no effect on intimal hyperplasia or arterial remodelling induced by balloon catheter injury in monkeys. J Am Coll Cardiol. 1998;31:1158–1164[Abstract/Free Full Text]
  28. Levine RL, Chen SJ, Durand J, Chen YF, Oparil S. Medroxyprogesterone attenuates estrogen-mediated inhibition of neointima formation after balloon injury of the rat carotid artery. Circulation. 1996;94:2221–2227[Abstract/Free Full Text]
  29. Oparil S, Levine RL, Chen SJ, Durand J, Chen YF. Sexually dimorphic response of the balloon-injured rat carotid artery to hormone treatment. Circulation. 1997;95:1301–1307[Abstract/Free Full Text]
  30. Brewster ME, Hora MS, Simpkins JW, Bodor N. Use of 2-hydroxypropyl-beta-cyclodextrin as a solubilizing and stabilizing excipient for protein drugs. Pharm Res. 1991;8:792–795[CrossRef][Medline]
  31. Frijlink HW, Visser J, Hefting NR, Oosting R, Meijer DKF, Lerk CF. The pharmacokinetics of beta-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin in the rat. Pharm Res. 1990;7:1248–1252[CrossRef][Medline]
  32. Kristinsson JK, Fridriksdottir H, Thorisdottir S, Sigurdardottir AM, Stefansson E, Loftsson T. Dexamethasone-cyclodextrin-polymer co-complexes in aqueous eye drops: aqueous humor pharmacokinetics in humans. Invest Opthalmol Vis Sci. 1996;37:1199–1203[Abstract/Free Full Text]
  33. Doenicke A, Roizen MF, Nebauer AE, Kugler A, Hoernecke R, Beger-Hintzen H. A comparison of two formulations for etomidate, 2-hydroxypropyl-beta-cyclodextrin (HPCD) and propylene glycol. Anesth Analg. 1994;79:933–939[Abstract/Free Full Text]
  34. O’Keefe JH, Kim SC, Hall RR, Cochran VC, Lawhorn SL, McCallister BD. Estrogen replacement therapy after coronary angioplasty in women. J Am Coll Cardiol. 1997;29:1–5[Abstract]
  35. O’Brien JE, Peterson ED, Keeler GP, et al. Relation between estrogen replacement therapy and restenosis after percutaneous coronary interventions. J Am Coll Cardiol. 1996;28:1111–1118[Abstract]
  36. Wolf MG, Jang Y, Penn MS, et al. Quantitative evaluation of local drug delivery using the InfusaSleeve catheter. Cathet Cardiovasc Diagn. 1997;42:102–108[CrossRef][Medline]
  37. Yang LY, St. Pierre J, Scherrer DE, Lasala JM, Walsh RG, Abendschein DR. Comparison of methods for local delivery of tissue factor pathway inhibitor to balloon-injured arteries in rabbits. Coron Artery Dis. 1999;10:327–333[Medline]
  38. Murad F, Kuret JA. Estrogens and progestins. Gilman AG, Rall TW, Nies AS, Taylor P. The Pharmacological Basis of Therapeutics. New York: Pergamon Press; 1990. p. 1384–1412



This article has been cited by other articles:


Home page
 J EndocrinolHome page
I. C Villar, A. J Hobbs, and A. Ahluwalia
Sex differences in vascular function: implication of endothelium-derived hyperpolarizing factor
J. Endocrinol., June 1, 2008; 197(3): 447 - 462.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
C. Filipe, L. Lam Shang Leen, L. Brouchet, A. Billon, V. Benouaich, V. Fontaine, P. Gourdy, F. Lenfant, J.-F. Arnal, A.-P. Gadeau, et al.
Estradiol accelerates endothelial healing through the retrograde commitment of uninjured endothelium
Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2822 - H2830.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
T. Adriaenssens, J. Mehilli, R. Wessely, G. Ndrepepa, M. Seyfarth, A. Wieczorek, B. Blaich, R. Iijima, J. Pache, A. Kastrati, et al.
Does Addition of Estradiol Improve the Efficacy of a Rapamycin-Eluting Stent?: Results of the ISAR-PEACE Randomized Trial
J. Am. Coll. Cardiol., March 27, 2007; 49(12): 1265 - 1271.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
Y. D. Krom, N. M.M. Pires, J. W. Jukema, M. R. de Vries, R. R. Frants, L. M. Havekes, K. W. van Dijk, and P. H.A. Quax
Inhibition of neointima formation by local delivery of estrogen receptor alpha and beta specific agonists
Cardiovasc Res, January 1, 2007; 73(1): 217 - 226.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
A. Abizaid, M. Albertal, M. A. Costa, A. S. Abizaid, R. Staico, F. Feres, L. A. Mattos, A. G. M. R. Sousa, J. Moses, N. Kipshidize, et al.
First human experience with the 17-beta-estradiol-eluting stent: The estrogen and stents to eliminate restenosis (EASTER) trial
J. Am. Coll. Cardiol., March 17, 2004; 43(6): 1118 - 1121.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
P. Geraldes, M. G. Sirois, and J.-F. Tanguay
Specific Contribution of Estrogen Receptors on Mitogen-Activated Protein Kinase Pathways and Vascular Cell Activation
Circ. Res., September 5, 2003; 93(5): 399 - 405.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
P. Geraldes, M. G. Sirois, P. N. Bernatchez, and J.-F. Tanguay
Estrogen Regulation of Endothelial and Smooth Muscle Cell Migration and Proliferation: Role of p38 and p42/44 Mitogen-Activated Protein Kinase
Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1585 - 1590.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
B. Chandrasekar, S. Nattel, and J.-F. Tanguay
Coronary artery endothelial protection after local delivery of 17{beta}-estradiol during balloon angioplasty in a porcine model: a potential new pharmacologic approach to improve endothelial function
J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1570 - 1576.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chandrasekar, B.
Right arrow Articles by Tanguay, J.-F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chandrasekar, B.
Right arrow Articles by Tanguay, J.-F.

HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK