ROLE OF SMOOTH MUSCLE CELLS IN GRAFT INTIMAL HUPERPLASIA

我们研究的长期目标是通过控制血管内膜增生来改善人工血管的通畅性。内膜增生以平滑肌细胞（SMC）积累和基质沉积为特征，在吻合口附近最为严重。吻合口内膜增生的原因尚不清楚。我们提出氧化修饰的脂质和脂蛋白在血管移植失败中起作用，因为脂质氧化产物在假体移植物中积累，氧化低密度脂蛋白（oxLDL）具有许多对移植物愈合不利的特性，包括刺激SMC增殖和细胞外基质的产生。我们的初步研究记录了假体移植物中的脂质氧化产物，与主动脉SMC相比，假体移植物培养的SMC产生高水平的PDGF和胶原蛋白，以及oxLDL刺激移植物而非主动脉SMC产生PDGF的能力。基于这些发现，我们提出oxLDL诱导多种病理过程，包括通过移植物SMC刺激PDGF的产生，进而刺激胶原的产生。这些细胞功能的改变可能导致吻合口内膜增生，最终导致合成血管移植失败。我们将通过体外研究oxLDL对主动脉和移植物SMC生成PDGF和胶原合成的影响来验证这一假设。将比较主动脉和移植物SMC在氧化低密度脂蛋白刺激下产生PDGF的特点。oxLDL发挥其作用的机制，包括活性氧的作用，将被解决。下一步，我们将研究PDGF对SMC生成胶原的影响。最后，我们将研究oxLDL对主动脉和移植物SMC胶原生成的影响。oxLDL刺激SMC胶原生成的机制，包括生长因子和活性氧的作用将被评估。SMC积累和细胞外基质的产生在内膜增生的发展中都是至关重要的。所提出的研究将有助于更好地理解脂质和SMC在移植物衰竭的病理生理中的作用。这将为未来在体内研究诸如膳食抗氧化剂等疗法控制脂质氧化和促进移植物愈合的功效奠定基础。最终，这可能导致抑制吻合口内膜增生发展的治疗。

The long-term goal of our research is to improve patency of prosthetic vascular grafts by controlling intimal hyperplasia. Intimal hyperplasia is characterized by smooth muscle cell (SMC) accumulation and matrix deposition, and is most severe adjacent to the anastomoses of prosthetic grafts. The cause of anastomotic intimal hyperplasia is not known. We propose that oxidatively-modified lipids and lipoproteins play a role in vascular graft failure since lipid oxidation products accumulate in prosthetic grafts, and oxidized low density lipoprotein (oxLDL) possesses a number of properties which would adversely affect graft healing, including stimulation of SMC proliferation and extracellular matrix production. Our preliminary studies document lipid oxidation products in prosthetic grafts, high levels of PDGF and collagen production by SMC cultured from prosthetic grafts compared to aortic SMC, and the ability of oxLDL to stimulate PDGF production by graft but not aortic SMC. Based on these findings, we propose that oxLDL induces multiple pathologic processes, including stimulation of PDGF production by graft SMC which in turn stimulates collagen production. These alterations in cellular function may result in the development of anastomotic intimal hyperplasia, and eventual failure of synthetic vascular grafts. We will test this hypothesis by studying the effect of oxLDL on PDGF production and collagen synthesis by aortic and graft SMC in vitro. The characteristics of oxLDL-stimulated PDGF production by aortic and graft SMC will be compared. The mechanism by which oxLDL exerts its effect, including the role of reactive oxygen species, will be addressed. Next, the effect of PDGF on collagen production by SMC will be investigated. Finally, the effect of oxLDL on collagen production by aortic and graft SMC will be studied. The mechanism by which oxLDL stimulates SMC collagen production, including the role of growth factors and reactive oxygen species will be assessed. Both SMC accumulation and extracellular matrix production are critical in the development of intimal hyperplasia. The proposed studies will lead to a better understanding of the role of lipids and SMC in the pathophysiology of graft failure. This will set the stage for future in vivo studies on the efficacy of therapies, such as dietary antioxidants, to control lipid oxidation and promote graft healing. Ultimately, this may lead to treatments which will inhibit the development of anastomotic intimal hyperplasia.