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

近年来，血管危险因素促进脑血管并发症的发展并对认知功能产生影响已变得越来越明显。其中，高血压是一个主要的可改变的风险因素，因为大脑是血压变化引起器官损伤的早期目标。随后，高血压和低血压（尤其是老年人）都与认知功能下降有关，这引发了关于血压控制作为实现最佳脑灌注的潜在治疗策略的争议性讨论，从而减少认知功能障碍的发生。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，以分离有效的治疗靶点，以预防和最重要的是逆转高血压介导的认知功能下降。在这方面，我们最近的研究结果强烈支持这一假设，即调节鞘氨醇-1-磷酸（S1 P）及其生成酶（SphK 2）具有作为抗高血压治疗的潜力，也可能逆转已建立的认知功能障碍。在脑微循环中，S1 P具有血管收缩效力并调节免疫细胞与血管壁相互作用的关键内皮功能，这赋予S1 P信号传导在控制血流自动调节中具有实质性的重要性。血管壁应力由例如，已经描述了增加的壁张力、活性氧物质或促炎细胞因子激活S1 P生成酶以产生S1 P，S1 P又直接或间接调节血管功能，对脑灌注具有深远的影响，并因此影响认知能力。初步数据表明，在小鼠中，SphK活性的变化，因此，在脑S1 P浓度，影响脑灌注，神经元形态和记忆功能，这支持了研究表明，S1 P浓度升高和神经元死亡之间的显着相关性和S1 P信号参与学习过程。这促使我们推测，S1 P稳态的任何紊乱（例如，高血压期间SphK 2失调引起的）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。除了高血压之外，这对于伴随组织S1 P浓度和认知功能改变的病理学尤其相关，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.