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

Abstract

Background: Percutaneous transluminal coronary angioplasty (PTCA) and stent implantation are associated with intimal hyperplasia and extracellular matrix (ECM) accumulation, resulting in restenosis. We showed that local delivery of 17-beta-estradiol (17βE) reduced restenosis following PTCA and stent implantation by 47 and 23%, respectively. Because estrogens decreased type I and type III collagen synthesis in vitro, we hypothesized that local delivery of 17βE may influence intimal hyperplasia formation by modulating ECM expression. Methods: Porcine coronary arteries underwent PTCA or stenting and were randomly assigned to 17βE or placebo. After 28 days, animals were sacrificed for histology and collagen type I and III content analysis. Results: Both collagen subtypes increased in the media by 1.7 to 2.6-fold after PTCA and by 15.7 to 16.1-fold after stenting, as compared to PTCA segments. In the neointima, the ratio of collagen type III to type I was 2.7 in stented arteries and only 0.3 in PTCA arteries. In the neointima of 17βE-treated animals, collagen type I (but not type III) content upregulation was limited by 53% after PTCA and by 74% after stenting. Conclusion: Local delivery of 17βE reduces restenosis, in part by decreasing the density of collagen type I in the neointima in PTCA and stented arteries.

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

“…The increase of collagen type III in response to estrogen administration was found in hearts of aged and Dahl salt-sensitive rats (8,61). Similar estrogenic effects on collagen III were demonstrated in the arteries and other tissues of ovariectomized animals (7,10,15,24,36,47). The mechanisms of enhanced collagen type III expression due to estrogen treatment are still unknown, but they are likely related to the changes in MMPs and TIMPs expression that we Fig.…”

GPER–novel membrane oestrogen receptor

“…Female Sprague-Dawley rats are protected from carotid balloon injury compared with males, and this sex difference is abolished by ovariectomy but not castration (58). Local delivery of estradiol decreases coronary angioplasty-induced neointimal hyperplasia in pigs (59, 60). These studies led to the development of estrogen-eluting stents, which reduce neointimal proliferation and induce reendothelialization in rabbit aorta (61) and porcine coronary artery (62).…”

Macromolecular Approaches to Prevent Thrombosis and Intimal Hyperplasia Following Percutaneous Coronary Intervention

“…85−87 Alternatively, pro-healing biologics, which are characterized by their ability to support re-endothelialization of the arterial wall, have been reported to minimize the extent of SMC proliferation, platelet adhesion, and collagen synthesis. 19,88−90 Still, this class of antirestenotic therapeutics does not attenuate every aspect of restenosis; adverse inflammatory responses, 91,92 as well as decreased vasoconstrictive properties of injured vessels, 93 have resulted after treatment with pro-healing drugs. Therefore, as each of the four classes of antirestenotic therapeutics demonstrates detriments for the prevention of restenosis regardless of systemic delivery or local delivery via stents or coated balloons, there is a need to develop new approaches to combat thrombosis and neointimal hyperplasia.…”