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

• Applicant: Professor Dr. Gabor Petzold, since 7/2017
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Human Cognitive and Systems Neuroscience ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 315229332

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.

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Professorin Dr. Anja Meissner, until 7/2017