Resistance to Apoptosis in Smooth Muscle Cells and Stent-Induced Stenosis in Coronary and Peripheral Arteries
Occlusive vascular disease is one of the major causes of morbidity and mortality in the United States. Treatment often involves angioplasty and stenting. In 30-50% of angioplasty cases, success is limited by re-narrowing (restenosis) of the artery. Stenting offers the advantage of a slightly lower restenosis rate. However, this rate is still significant. Studies aimed at further understanding the restenotic disease process and the cells that contribute to it would aid in the development of treatment options. The restenotic process involves the proliferation, apoptosis and migration of vascular smooth muscle cells (VSMCs). Apoptosis has been shown to be an integral part of lesion development in atherosclerosis and restenosis after angioplasty. Subsequently, alterations in this process could significantly affect and determine the extent of lesion development. It was hypothesized that arteries from alternate embryological origins react differently with regards to the development of in-stent stenosis and that vascular smooth muscle cells derived from different arteries are unique with regards to their apoptotic responses. To test these hypotheses, in vivo studies were performed comparing central and peripheral arteries in a swine model of stenting and in vitro studies were done looking at apoptotic responses of human coronary and aortic VSMCs. Swine studies of stenosis after stenting demonstrated a significantly higher level of intimal area development in coronary arteries compared to the peripheral internal iliac arteries. There was an increase in percent lumen stenosis and maximal intimal thickness; however, these differences did not reach statistical significance. Utilizing in vitro studies on VSMCs, celis derived from human coronary arteries demonstrated a higher level of resistance to staurosporine-induced apoptosis than human aortic VSMCs. This observation was confirmed using calphostin C mediated VSMC apoptosis. IGF-1, an anti-apoptotic growth factor for VSMCs, was found to be more effective at protecting VSMCs derived from coronary arteries as compared to those derived from aortic arteries. In an effort to identify possible factors that may contribute to this effect, expression levels of various proteins of apoptotic interest were measured by western blot analysis. PKC s and bad exhibited significantly higher levels of expression in aortic VSMCs. Bax exhibited non significantly elevated levels in aortic VSMCs while expression of PKC a, PKC 8, bclxL and bcl-2 did not differ between the two cell lines. The findings of these investigations demonstrated that (1) in comparison to internal iliac arteries, coronary arteries have a higher tendency towards intimal hyperplasia after stenting and (2) in comparison to aortic VSMCs, coronary VSMCs are more resistant to apoptosis. This study identified differences between arteries that may affect the outcome of restenotic lesions in clinical practice. Further knowledge in this area could lead to new therapies as well as beneficial changes in the way vascular interventional procedures are performed. A trait known to influence restenosis in one artery may serve as a pharmacological target in another artery that does not express the same characteristic.
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