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

Abstract

In the current study, we investigated the effect of local intravascular delivery of 17beta-estradiol (17beta-E) on subsequent in-stent neointimal hyperplasia. Twenty-seven stents were implanted in coronary arteries of juvenile swine. Coronary arteries were randomized to local treatment with 17beta-E or no drug therapy (control-vehicle treated). Twenty-eight days post-treatment, 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 17beta-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 17beta-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 17beta-E-treated arteries. Finally, we observed a correlation between neointimal hyperplasia and inflammation score, which in turn, was inversely related to reendothelialization. Locally delivered, 17beta-E is inhibiting the inflammatory response and smooth muscle cells proliferation and improving vascular reendothelialization which together are contributing to reduce in-stent restenosis in a porcine coronary injury model. Together, these data demonstrate the potential clinical application of 17beta-estradiol to improve vascular healing and prevent in-stent restenosis.

Local Delivery of 17-Beta-Estradiol Modulates Collagen Content in Coronary Porcine Arteries after PTCA and Stent Implantation

“…Therefore, new strategies are required for better long-term prognosis and restenosis prevention. Our group previously demonstrated that local delivery of a single bolus of 17βE reduced restenosis after PTCA and stent implantation by reducing PCNA-positive VSMC numbers and the inflammation process [13, 14]. In this study, we reported a significant difference in the ratio of collagen type III to type I in the neointima between PTCA (where collagen type I predominates) and stent implantation (mostly collagen type III).…”

“…When compared with control vehicle-treated groups, arterial segments treated with local delivery of 17βE showed a significant reduction of morphometric area stenosis, from 30 to 16% for PTCA and from 71 to 55% for stent, which represented a decrease of 47 and 23%, respectively (table 1). Previous work from our laboratory has demonstrated that local delivery of 17βE significantly decreases the number of proliferating cell nuclear antigen (PCNA)-positive VSMC after PTCA or stent implantation [13, 14]. Based on these results, we evaluated VSMC density in the media and the neointima at post-procedure day 28.…”

“…We previously demonstrated that local delivery of 17βE prevented restenosis formation after PTCA and stent implantation [13, 14]. Therefore, we evaluated if these effects of local delivery of 17βE were in part due to the reduction of collagen type I and type III content.…”

“…Following two 30 s balloon inflations at 10 atm of 3 coronaries (the left anterior descending, circumflex, and right coronary arteries), each animal was randomized to receive either local delivery of 100 µg/kg of 17βE [number of arteries treated (n) = 28], 200 µg/kg of 17βE (n = 14) or vehicle [2-hydroxypropyl-β-cyclodextrin (HPCD); n = 27]. The HPCD-coated 17βE (Sigma) or vehicle, in a total volume of 5 ml, was delivered using the InfusaSleeve Catheter (LocalMed, Inc., Palo Alto, Calif., USA) at a driving pressure of 10 atm supported by balloon pressure of 6 atm, as previously described [14]. After the infusion, a slotted tubular stent (7 mm long; Palmaz-Schatz, Johnson & Johnson) was then deployed at a higher pressure of 14 atm for 30 s to achieve a stent to artery ratio of 1.3–1.4:1 and to provide optimized stent expansion as performed under clinical conditions.…”

Estrogen-Stimulated Endothelial Repair Requires Osteopontin

“…33 Neointima formation after acute endovascular injury is inhibited by E 2 supplementation and different mechanisms have been proposed including inhibition of SMC migration and proliferation, and stimulation of reendothelialization. 12,38 Interestingly, it was suggested by an in vitro study that E 2 inhibits OPN expression in SMCs, which is required for adventitial fibroblast migration involved in intimal thickening. 18 In addition, our data show that E 2 mediates the acceleration of endothelial repair through an OPN-dependent pathway suggesting dual opposite roles for OPN in SMCs and ECs, which both contribute to neointima inhibition.…”