Role of PTEN in Vascular Lesion Formation

再狭窄的特征是动脉内膜中的平滑肌细胞(SMC)通过 内侧来源的SMC去分化、迁移和增殖。一种炎症反应，特征是 通过骨髓源性和/或循环炎性细胞和祖细胞向受损血管募集， 也会导致再狭窄。几种趋化因子，包括MCP-1/JE，SDF-1，IL-6和CXCL1/KC，是 在损伤后的SMC中迅速诱导，并通过招募 炎性和血管前体细胞。其中一些因素也被证明直接影响到 SMC本身的生物学功能，使SMC既是损伤反应的中介者，又是损伤反应的效应者。 然而，在SMC中激活的反应损伤的潜在分子程序还没有明确的定义。 我们以前的工作表明，SMC特异性的PTEN失活，PI3-激酶信号的负调节因子，是 早期触发因素导致血管病变的形成。我们获得了可诱导的SMC特异性PTEN突变小鼠 (PTEN Iko)，并发现，与对照组相比，PTEN Iko小鼠的总PTEN显著减少 在主要血管中，伴随着磷酸化Akt水平的升高和术后新生内膜的形成 颈动脉损伤。PTEN基因缺陷的体外培养的SMC在基础状态下呈现自分泌生长表型 条件和表达的细胞因子/趋化因子图谱与实验后在SMC中观察到的相似 受伤。初步数据显示，PTEN缺失可激活转录因子NF？B和HIF-1？； 抑制NFB或HIF-1可阻断PTEN缺失所介导的特异性趋化因子的上调。在……上面 另一方面，我们的初步数据表明，SMC中的核受体PPAR？激活 上调PTEN，因此我们的研究将检测PPAR？激活抑制SMC的能力 通过上调SMC PTEN的表达，促进细胞增殖，调节抗炎反应。总的来说，我们的 初步数据提供证据表明，SMC PTEN信号的改变是一个关键的启动 通过化学诱导剂家族的产生驱动病理性血管重塑的决定因素 通过旁分泌机制招募炎性/前体细胞并促进自分泌SMC 增生性反应。因此，SMC PTEN信号的恢复有望逆转SMC PTEN信号的级联反应 由血管损伤引起的事件。我们将确定PTEN的后果和作用机制 PTEN缺失培养的SMC产生祖细胞/炎性细胞介质的损失 小鼠SMC特异性PTEN缺失在趋化因子诱导的SMC增殖中的相对作用 实验性血管新生内膜形成过程中祖细胞和炎性细胞的募集 目标一号受伤。在第二个目标中，我们将确定PPAR激动剂在上调PTEN和 SMC的生物学功能及PTEN调节在介导SMC保护作用中的作用 PPAR？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.