Role of PTEN in Vascular Lesion Formation

呼吸暂停的特征是平滑肌细胞（SMC）通过血管内皮细胞在动脉内膜中的聚集。 脱分化、迁移和中膜SMC增殖。一种炎症反应，其特征在于 通过骨髓来源的和/或循环的炎性和祖细胞募集到受损血管， 也会导致再狭窄。几种趋化因子，包括MCP-1/JE，SDF-1，IL-6和CXCL 1/KC， 在SMC损伤后迅速诱导，并通过募集 炎症和血管祖细胞。其中一些因素也被证明直接影响 SMC本身的生物学功能将SMC作为损伤反应的介质和效应器。 然而，在SMC中激活的响应于损伤的潜在分子程序尚未明确定义。 我们以前的工作表明SMC特异性的PTEN失活，一种PI 3激酶信号的负调节因子， 早期触发器驱动血管损伤形成。我们建立了诱导型SMC特异性PTEN突变小鼠， (PTEN iKO），并发现与对照相比，PTEN iKO小鼠表现出总PTEN的显著减少， 在大血管中，伴随磷酸化Akt水平增加和新生内膜形成增加， 颈动脉损伤PTEN缺陷的SMC在体外表现出自分泌生长的表型，在基础培养基中， 条件下，并表达细胞因子/趋化因子谱类似于在SMC中观察到的实验后， 损伤初步数据显示，PTEN缺失会激活转录因子NF â B和HIF-1 â; 抑制NF B或HIF-1阻断了由PTEN缺失介导的特异性趋化因子的上调。对 另一方面，我们初步数据表明，SMC核受体，过氧化物酶体增殖物激活受体， 因此，我们的研究将检查PPAR激活抑制SMC的能力 增殖和调节抗炎反应通过上调SMC的PTEN。总体而言，我们 初步数据提供了证据表明，SMC PTEN信号转导的改变是启动细胞凋亡的关键。 通过产生化学引诱物家族驱动病理性血管重塑的决定因子 其通过旁分泌机制募集炎性/祖细胞并促进自分泌SMC 增生反应。因此，预计SMC PTEN信号传导的恢复将逆转SMC凋亡的级联反应。 血管损伤引起的事件。我们将确定PTEN的作用后果和机制， 在培养的无PTEN的SMC中，SMC产生祖细胞/炎性细胞介质的损失，并评估 小鼠SMC特异性PTEN缺失对趋化因子诱导的SMC增生的相对贡献， 实验性血管损伤后新生内膜形成过程中祖细胞和炎性细胞的募集 目标1受伤在目的二，我们将确定过氧化物酶体增殖物激活受体激动剂对PTEN上调的作用， 平滑肌细胞的生物学功能，并确定PTEN调节在介导平滑肌细胞保护作用中的作用。 过氧化物酶体增殖物激活物受体激动剂对抗损伤诱导的血管重塑的发展。

Restenosis is characterized by smooth muscle cell (SMC) accumulation in the arterial intima through dedifferentiation, migration, and proliferation of medial-derived SMC. An inflammatory response, characterized by bone marrow-derived and/or circulating inflammatory and progenitor cell recruitment to the injured vessel, also contributes to restenosis. Several chemokines, including MCP-1/JE, SDF-1¿, IL-6, and CXCL1/KC, are rapidly induced in SMC following injury and participate in the remodeling process through the recruitment of inflammatory and vascular progenitor cells. Some of these factors have also been shown to directly affect the biological function of the SMC itself placing the SMC as both a mediator and an effector of the injury response. However, the underlying molecular programs activated in SMC in response to injury are not clearly defined. Our previous work indicates SMC-specific PTEN inactivation, a negative regulator of PI3-kinase signaling, is an early trigger driving vascular lesion formation. We generated inducible SMC-specific PTEN mutant mice (PTEN iKO) and found that, compared to controls, PTEN iKO mice exhibit significant reductions of total PTEN in major vessels with accompanying increased phosphoAkt levels and enhanced neointima formation following carotid arterial injury. PTEN-deficient SMC in vitro exhibit an autocrine growth phenotype under basal conditions and express a cytokine/chemokine profile similar to what is observed in SMC following experimental injury. Preliminary data show that PTEN depletion activates the transcription factors, NF¿B and HIF-1¿; inhibition of NF¿B or HIF-1¿ blocked the upregulation of specific chemokines mediated by PTEN depletion. On the other hand, our preliminary data suggest that activation of the nuclear receptor, PPAR¿, in SMC upregulates PTEN, therefore our studies will examine the ability of PPAR¿ activation to inhibit SMC proliferation and regulate anti-inflammatory responses through the upregulation of SMC PTEN. Overall, our preliminary data provide evidence that an alteration in SMC PTEN signaling serves as a key initiating determinant driving pathological vascular remodeling through the production of a family of chemoattractants that recruit inflammatory/progenitor cells through a paracrine mechanism and promote an autocrine SMC hyperplastic response. Therefore, restoration of SMC PTEN signaling is anticipated to reverse the cascade of events brought on by vascular injury. We will determine the consequences and mechanism of action of PTEN loss on SMC production of progenitor/inflammatory cell mediators in cultured PTEN null SMC and assess the relative contribution of SMC-specific deletion of PTEN in mice on chemokine-induced SMC hyperplasia and recruitment of progenitor and inflammatory cells during neointima formation following experimental vascular injury in Aim One. In Aim Two, we will determine the role of PPAR¿ agonists on the upregulation of PTEN and biological functions of SMC and determine the role of PTEN regulation in mediating the protective effects of PPAR¿ agonists against the development of injury-induced vascular remodeling.