Adenosine A1 receptors in neointimal hyperplasia and in-stent stenosis in Ossabaw miniature swine

Abstract

Stent-induced neointimal hyperplasia is a major cause of morbidity following stent deployment in patients with coronary artery disease. Importantly, however, mechanisms underlying stent-induced neointimal hyperplasia are unclear. This pathological response to stent placement is more aggressive when stents are over-expanded, suggesting that vascular injury may play a role. In this study we tested the hypothesis that adenosine A1 receptor upregulation is associated with neointimal hyperplasia within coronary artery stents. Adult male Ossabaw swine were used as our experimental model. Neointima formation and gene expression were studied 4 weeks after coronary stents were placed at 1.0x or 1.3x luminal diameter. Neointima formation was observed in 1.0x stents and more than doubled in 1.3x stents, thus verifying the response to overexpansion injury. A1 receptor mRNA was increased four-fold and seven-fold in stents at 1.0x and 1.3x luminal diameter, suggesting that increased A1 receptor activity might contribute to stent-induced neointimal hyperplasia. Coronary artery organ culture model of arterial injury demonstrated A1 receptor activation increased DNA synthesis three-fold, an effect abolished by A1 receptor antagonism. Our data indicate that A1 receptor expression is increased within stents and that activation of A1 receptors increases smooth muscle cell proliferation. We suggest that inhibition of A1 receptor signaling may be a promising therapeutic target for management of in-stent stenosis.