Hypertension-related cognitive deficits and sphingosine-1-phosphate (S1P) - pathophysiology and therapeutic significance

近年来，血管危险因素有助于脑血管并发症的发展，并对认知功能产生影响。其中，高血压是一个主要的可改变的危险因素，因为大脑是血压变化导致器官损伤的早期目标。随后，高血压和低血压，特别是在老年人中，都与认知能力下降有关，这引发了关于血压控制作为一种潜在的治疗策略以实现最佳脑灌注从而减少认知功能障碍发生的争议性讨论。然而，最近的随机对照试验研究了抗高血压治疗对认知能力的影响，结果却相互矛盾。根据目前的知识，很明显，迫切需要了解高血压诱导的脑血管并发症的潜在机制，以便分离有效的治疗靶点来预防，最重要的是逆转高血压介导的认知能力下降。在这方面，我们最近的研究结果有力地支持了鞘氨醇-1-磷酸（S1P）及其生成酶（SphK2）的调节具有抗高血压治疗的潜力，也可能逆转既定的认知功能障碍。已知S1P及其信号轴调节许多重要的血管和免疫细胞功能。在脑微循环中，S1P具有血管收缩效力并调节内皮功能，这对于免疫细胞与血管壁的相互作用至关重要，这使得S1P信号在控制血流自动调节中具有重要意义。据描述，由壁张力增加、活性氧或促炎细胞因子引起的血管壁应激可激活生成S1P的酶，从而产生S1P，进而直接或间接调节血管舒缩功能，对脑灌注产生深远影响，从而影响认知表现。初步数据表明，在小鼠中，SphK活性的变化以及大脑中S1P浓度的变化会影响脑灌注、神经元形态和记忆功能，这支持了S1P浓度升高与神经元死亡以及S1P信号参与学习过程之间存在显著相关性的研究。这促使我们推测，任何对S1P稳态的干扰（例如高血压期间SphK2的失调）都可能对血管、屏障和免疫细胞功能产生负面影响，从而可能损害脑血管功能，最终影响认知能力。除高血压外，这与伴有组织S1P浓度和认知功能改变的病理特别相关，例如，心力衰竭和中风。

In recent years, it has become evident that vascular risk factors contribute to the development of cerebrovascular complications with consequences for cognitive function. Among them, hypertension emerged as such a major modifiable risk factor since the brain is an early target for organ damage due to changes in blood pressure. Subsequently both high and, especially in the elderly, low blood pressure have been linked to cognitive decline, which initiated controversial discussions about blood pressure control as a potential therapeutic strategy to achieve optimal brain perfusion and thus, reduce the occurrence of cognitive dysfunction. Yet, recent randomized controlled trials examined the impact of anti-hypertensive therapy on cognitive performance with conflicting results. In light the current knowledge, it comes apparent that there is an urgent need to understand the underlying mechanisms of hypertension-induced cerebrovascular complications in order isolate effective therapeutic targets to prevent and most importantly also reverse cognitive decline mediated through hypertension. In this respect, our recent findings strongly support the hypothesis that the modulation of sphingosine-1-phosphate (S1P) and its generating enzyme (SphK2) holds potential to serve as anti-hypertensive therapy that might also reverse established cognitive dysfunction.S1P and its signaling axis is known to regulate a number of important vascular and immune cell functions. In the cerebral microcirculation, S1P holds vasoconstrictor potency and modulates endothelial functions critical for immune cell interaction with the vessel wall, which confers S1P signaling with substantial importance in the control of blood flow autoregulation. Vessel wall stress caused by e.g., increased wall tension, reactive oxygen species or pro-inflammatory cytokines, has been described to activate S1P generating enzymes to produce S1P that, in turn, directly or indirectly modulates vasomotor function with far-reaching consequences for cerebral perfusion and hence, cognitive performance. Preliminary data indicate that in mice, changes in SphK activity and thus, in cerebral S1P concentrations, affect brain perfusion, neuronal morphology and memory function, which supports studies showing a striking correlation between elevated S1P concentrations and neuronal death and an involvement of S1P signaling in learning processes. This spurs our speculation that any disturbance in the S1P homeostasis (e.g. induced by deregulation of SphK2 during hypertension) might hold potential to negatively affect vascular, barrier and immune cell function and thereby possibly distress cerebrovascular function and ultimately, cognitive performance. Apart from hypertension, this is particularly relevant for pathologies that are accompanied by alterations in tissue S1P concentration and cognitive function like for instance, heart failure and stroke.