Local delivery of 17β-estradiol improves reendothelialization and decreases inflammation after coronary stenting in a porcine model

Summary

In the current study, we investigated the effect of local intravascular delivery of 17β-estradiol (17β-E) on subsequent instent neointimal hyperplasia. Twenty-seven stents were implanted in coronary arteries of juvenile swine. Coronary arteries were randomized to local treatment with 17β-E or no drug therapy (control-vehicle treated). Twenty-eight days posttreatment, angiographic images revealed an improved minimal lumen diameter (2.2 ± 0.2 vs. 1.3 ± 0.2 mm, P < 0.005) and a reduction of late lumen loss (1.7 ± 0.2 vs. 2.3 ± 0.1 mm, P < 0.01) in 17β-E-treated vessels compared to control-vehicle treated. Histological analyses showed a reduction of stenosis (51.49 ± 6.75 vs.70.86 ± 6.24%, P < 0.05), mean neointimal thickness (0.51 ± 0.07 vs.0.83 ± 0.14 mm, P < 0.05) and inflammation score (1.29 ± 0.28 vs. 2.85 ± 0.40, P < 0.05) in 17β-E-treated arteries compared to control-vehicle treated arteries. Immunohistochemistry analyses revealed a reduction of proliferating smooth muscle cells and increased in-stent reendothelialization in 17β-E-treated arteries. Finally, we observed a correlation between neointimal hyperplasia and inflammation score, which in turn, was inversely related to reendothelialization. Locally delivered, 17β-E is inhibiting the inflammatory response and smooth muscle cells proliferation and improving vascular reendothelialization which together are contributing to reduce instent restenosis in a porcine coronary injury model. Together, these data demonstrate the potential clinical application of 17β-estradiol to improve vascular healing and prevent in-stent restenosis.

Keywords

Coronary disease - hormones - inflammation - restenosis - stents

• References

• 1 Fischman DL, Leon MB, Baim DS. et al. for the Stent Restenosis Study Investigators. A randomized comparision of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994; 331: 496-501.
• 2 Serruys PW, de Jaegere P, Kiemeneij F. et al. for the Benestent Study Group. A comparison of balloon-expandable- stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331: 489-95.
• 3 Hoffmann R, Mintz GS, Dussaillant GR. et al. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996; 94: 1247-54.
• 4 Sullivan Jr TR, Karas RH, Aronovitz M. et al. Estrogen inhibits the response-to-injury in a mouse carotid artery model. J Clin Invest 1995; 96: 2482-8.
• 5 Chen SJ, Li H, Durand J. et al. Estrogen reduces myointimal proliferation after balloon injury of rat carotid artery. Circulation 1996; 93: 577-84.
• 6 Chandrasekar B, Tanguay JF. Local delivery of 17-beta estradiol decreases neointimal hyperplasia following coronary angioplasty in porcine model. J Am Coll Cardiol 2000; 36: 1972-8.
• 7 Moura A, Lam JYT, Hebert D. et al. Intramural delivery of agent via a novel drugdelivery sleeve: histological and functional evaluation. Circulation 1995; 92: 2299305.
• 8 Hong MK, Kent KM, Mehran R. et al. Continuous subcutaneous angiopeptin treatment significantly reduces neointimal hyperplasia in a porcine coronary instent restenosis model. Circulation 1997; 95: 449-54.
• 9 Wolf E, Roser K, Hahn M. et al. Enzyme and immunohistochemistry on undecalcified bone and bone marrow biopsies after embedding in plastic: a new embedding method for routine application. Virchows Archiv A Pathol Anat 1992; 420: 17-24.
• 10 Carter AJ, Laird JR, Farb A. et al. Morphologic characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model. J Am Coll Cardiol 1994; 24: 1398-405.
• 11 Schwartz RS, Huber KC, Murphy JG. et al. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol 1992; 19: 267-74.
• 12 Geraldes P, Sirois MG, Tanguay JF. Specific contribution of estrogen receptors on mitogen-activated protein kinase pathways and vascular cell activation. Circ Res 2003; 93: 399-405.
• 13 Iafrati MD, Karas RH, Aronovitz M. et al. Estrogen inhibits the vascular injury response in estrogen receptor α-deficient mice. Nat Med 1997; 3: 545-8.
• 14 Karas RH, Hodgin JB, Kwoun M. et al. Estrogen inhibits the vascular injury response in estrogen receptor b-deficient female mice. Proc Natl Acad Sci USA 1999; 96: 151336.
• 15 New G, Moses JW, Roubin GS. et al. Estrogen-eluting, phosphorylcoline-coated stent implantation is associated with reduced neointimal formation but no delay in vascular repair in a porcine coronary model. Cathet Cardiovasc Intervent 2002; 57: 266-71
• 16 Abizaid A, Albertal M, Costa M. et al. First Human Experience With the 17-Beta-Estradiol-Eluting Stent. J Am Coll Cardiol 2004; 43: 1118-21.
• 17 Kornowski R, Hong MK, Tio FO. et al. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998; 31: 224-30.
• 18 Miller DD, Karim MA, Edwards WD. et al. Relationship of vascular thrombosis and inflammatory leukocyte infiltration to neointimal growth following porcine coronary artery stent placement. Atherosclerosis 1996; 124: 145-55.
• 19 Garcia-Duran M, de Frutos T, Diaz-Recasens J. et al. Estrogen stimulates neuronal nitric oxide synthase protein expression in human neutrophils. Circ Res 1999; 85: 1020-6.
• 20 Miyamoto N, Mandai M, Suzuma I. et al. Estrogen protects against cellular infiltration by reducing the expression of E-selectin and IL6 in endotoxin-induced uveitis. J Immunol 1999; 163: 374-9.
• 21 Kastrati A, Koch W, Berger PB. et al. Protective role against restenosis from an interleukin-1 receptor antagonist gene polymorphism in patients treated with coronary stenting. J Am Coll Cardiol 2000; 36: 2168-73.
• 22 Weiner CP, Lizasoain I, Baylis SA. et al. Induction of calcium-dependent nitric oxide synthases by sex hormones. Proc Natl Acad Sci USA 1994; 91: 5212-6.
• 23 Hayashi T, Yamada K, Esaki T. et al. Estrogen increases endothelial nitric oxide by a receptor-mediated system. Biochem Biophys Res Commun 1995; 214: 847-55.
• 24 Chandrasekar B, Nattel S, Tanguay JF. Coronary artery endothelial protection following local delivery of 17β-estradiol during balloon angioplasty in a porcine model: a potential new pharmacological approach to improve endothelial function. J Am Coll Cardiol 2001; 38: 1570-6.
• 25 Cornwell TL, Arnold E, Boerth NJ. et al. Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP. Am J Physiol 1994; 267: C1405-13.
• 26 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: 916-26.
• 27 Murad F, Kuret JA. Estrogens and progestins. Gilman AG, Rall TW, Nies AS, Taylor P. The Pharmacological Basis of Therapeutics. NewYork: Pergamon Press; 1990: 1384-412.
• 28 Iakovou I, Schmidt T, Bonizzoni E. et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005; 293: 2126-30.