Galectin-glycan axis linking placental insufficiency and cardiovascular maladaptation (cardio-placenta axis): The role of vessel pathology

胎盘发育涉及母体细胞和高度糖化的胎儿滋养层细胞之间的复杂相互作用。这一过程的失败会导致先兆子痫(PE)，这是妊娠期最常见和致命的高血压并发症之一。PE病史会使母亲和孩子在以后的生活中患心血管疾病(CVD)的风险增加两到四倍。虽然PE和慢性血管疾病之间的联系是明确的，但这种联系的机制尚不清楚。Galectins(GAL)是糖码的通用翻译者，参与调节关键的生殖过程(胎盘形成、免疫耐受和血管生成)和心血管健康。一些研究表明，与GAL-1失调相关的胎盘糖码和胎盘生理改变与人类和小鼠的PE有关。这些数据表明，深入分析妊娠期间的多糖/半乳糖信号网络可以确定PE发生的分子途径，并直接促进心血管疾病的发病。因此，糖码是心脏-胎盘轴功能的分子总开关。这为设计PE诊断和管理策略以及改善妇女及其后代的长期心血管健康提供了新的机会。这项提议试图破解胎盘糖码，解开胎盘组织中与PE和CVD相关的糖基相互作用的结构框架和识别策略。此外，我们的目标是表征特定的多糖/半乳糖凝集素信号，这种信号有助于持久的内皮功能障碍和有PE病史的女性心血管疾病风险的增加。我们想通过病理应变和应变率来研究病理性糖码是否会导致心脏微血管功能障碍和稀疏，从而导致舒张期功能障碍。我们推测肺栓塞后的心血管病变是由糖码引起的心脏小血管病变引起的。由于糖码是多种因素共同作用的结果，揭示心脏胎盘轴可能有助于确定预防经历PE的妇女和子女心血管疾病进展的策略。

Placental development involves a complex interaction between maternal cells and heavily glycosylated foetal trophoblasts. Failure of this process can cause preeclampsia (PE), one of the most common and deadly hypertensive complications of pregnancy. A history of PE increases cardiovascular disease (CVD) risk by two to four times for mother and child later in life. While the association between PE and chronic vascular disease is clear, the mechanism for this association is not known. Galectins (gal) are versatile translators of the glycocode, involved in regulating key reproductive processes (placentation, immune tolerance and angiogenesis) and cardiovascular health. Several studies have shown that an altered placental glycocode and placenta physiology associated with gal-1 dysregulation is linked to PE in humans and mice. These data suggest that an in-depth analysis of glycan/galectin signalling networks in pregnancy can define the molecular routes through which PE develops and contribute directly to cardiovascular disease pathogenesis. Therefore, the glycocode is a molecular master switch for a functional cardio-placental axis. This offers new opportunities for designing PE diagnosis and management strategies and improving long-term cardiovascular health in women and their offspring. This proposal seeks to crack the placental glycocode, unravelling the structural frameworks and recognition strategies of sugar-based interactions in placental tissue that relate to PE and CVD. Additionally, we aim to characterise the specific glycan/galectin signature that contributes to lasting endothelial dysfunction and an elevated risk of cardiovascular disease in women with a history of PE. We want to investigate if a pathological glycocode induces cardiac microvascular dysfunction and rarefaction, which leads to diastolic dysfunction with a pathological strain and strain rate. We hypothesize that the cardiovascular pathology after PE is caused by glycocode-induced cardiac small vessel disease. Since the glycocode is a concerted interplay of a multitude of factors, unravelling the cardio-placental axis will potentially contribute to identify strategies to prevent the progression of cardiovascular disease in women and offspring that experience PE.