ROLE OF SMOOTH MUSCLE CELLS IN GRAFT INTIMAL HUPERPLASIA

我们研究的长期目标是通过控制内膜增生来改善人造血管移植物的通畅性。血管内膜增生以平滑肌细胞(SMC)堆积和基质沉积为特征，在人工血管吻合口附近最为严重。吻合口内膜增生的原因尚不清楚。我们认为氧化修饰的脂质和脂蛋白在血管移植物中起一定作用，因为脂质氧化产物在移植物中积累，而氧化低密度脂蛋白(OxLDL)具有一系列对移植物愈合不利的特性，包括刺激SMC增殖和产生细胞外基质。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，假体移植物中培养的SMC产生高水平的PDGF和胶原，以及oxLDL刺激移植物而不是主动脉SMC产生PDGF的能力。基于这些发现，我们认为oxLDL诱导了多种病理过程，包括移植物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的发展，并最终导致人造血管移植物的失败。我们将通过研究oxLDL对体外培养的主动脉和移植物SMC产生PDGF和合成胶原的影响来验证这一假说。比较oxLDL刺激的主动脉和移植物SMC产生PDGF的特点。将讨论oxLDL发挥作用的机制，包括活性氧物种的作用。接下来，我们将研究PDGF对SMC产生胶原蛋白的影响。最后，我们将研究oxLDL对主动脉和移植物SMC产生胶原的影响。氧化低密度脂蛋白刺激SMC胶原生成的机制，包括生长因子和活性氧物种的作用将被评估。SMC的积聚和细胞外基质的产生在内膜增生症的发生发展过程中起着关键作用。建议的研究将有助于更好地理解脂质和SMC在移植物失败的病理生理学中的作用。这将为未来体内研究饮食抗氧化剂等治疗方法的有效性奠定基础，以控制脂肪氧化和促进移植物愈合。最终，这可能导致治疗将抑制吻合口内膜增生的发展。

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.