GSP损伤海绵体血管内皮诱导勃起功能障碍发生的机制研究

Penile cavernous vascular endothelial injury plays an important role in the pathogenesis of erectile dysfunction (ED). Although it is proposed that cavernous vascular endothelium is vulnerable to injury than other cardiovascular endothelium, the exact mechanism by which ED occurs prior to systemic vascular diseases remains to be elucidated. Our previous study has shown that glycosylated serum protein (GSP) can be used as an early marker for endothelial function in young ED patients. We also found that GSP can lead to cavernous endothelial dysfunction but has less effect on cardiovascular and cerebrovascular endothelial cells. Our data also suggested that the phosphorylation of Cx43 and eNOS by PI3K-Akt signaling might be involved in GSP-induced cavernous endothelial dysfunction. We hypothesized that GSP is able to induce cavernous vascular endothelium-derived ED by targeting PI3K-Akt signaling pathway. Here, we would like to establish animal disease model and compare the differences among cardiovascular, cerebrovascular and cavernous vascular endothelium in terms of endothelial-dependent vasodilatation, eNOS and Cx43 expression and so on. Furthermore, we would like to explore the phosphorylation sites of Cx43and eNOS regulated by PI3K-Akt signaling pathway and the site-specific role in regulating Cx43 channel function and eNOS activity. Our study will not only shed new light on the molecular mechanism by which GSP induce cavernous endothelial injury and ED, but also provide experimental and theoretical basis to understand why ED often precedes the occurrence of other systemic vascular diseases.

阴茎海绵体血管内皮损伤是勃起功能障碍（ED）的重要病因。海绵体血管内皮容易受损被视为ED早于其他心血管病的关键所在，但海绵体血管内皮早期容易受损的机理仍未阐明。我们前期研究发现糖化血清蛋白（GSP）可作为年轻人血管内皮源性ED的一种早期标记物，其可早期损伤海绵体血管内皮而对心脑血管内皮影响较小，且该机制与PI3K-Akt介导的Cx43及eNOS磷酸化有关。由此我们提出“GSP可能通过抑制PI3K-Akt通路而诱发血管内皮源性ED”这一假说。本项目拟在前期工作基础上，建立病变动物模型并分析海绵体血管与心脑血管在功能、结构及Cx43、eNOS表达上的差异，深入研究GSP对PI3K-Akt通路的调控作用，包括对下游Cx43、eNOS磷酸化位点及Cx43通道、eNOS活性的影响。本项目研究将进一步阐明GSP损伤海绵体血管内皮并导致ED的分子机制，为揭示ED早发于其他心血管病提供实验数据和理论依据。

阴茎海绵体血管内皮损伤是勃起功能障碍（ED）的重要病因。海绵体血管内皮容易受损被视为ED早于其他心血管病的关键所在，但海绵体血管内皮早期容易受损的机理仍未阐明。本项目研究内容主要包括建立高糖基化蛋白（GSP）病变动物模型并分析海绵体血管与心脑血管在功能、结构及Cx43、eNOS表达上的差异，研究GSP对PI3K-Akt通路的调控作用，以及GSP对下游Cx43、eNOS磷酸化位点及Cx43通道、eNOS活性的影响。研究中成功构建了高浓度GSP病损模型，并动态观察了体内各系统血管内皮受损过程，检测到Cx43、eNOS、PI3K、Akt等各项指标变化情况，这些研究结果不仅阐明糖代谢异常导致ED的病理机制，也为海绵体血管损伤为何要早于其他系统血管损伤的机制提供了直接证据。研究实验结果还显示GSP可能是早期内皮功能损伤的致病因子，且其致病机理的核心机制可能与Cx43磷酸化改变密切相关，这就提示针对Cx43磷酸化的调控有利于阴茎血管内皮功能损伤的预防和修复，可为ED的防治提供可靠的依据。深入研究发现，特异性Cx43 Ser368磷酸化位点异常可能是糖代谢异常损伤血管内皮细胞的重要机制，针对此磷酸化位点的干预可为血管性ED提供精准治疗，对ED及心血管疾病的防治更有价值。