Hypertension-related cognitive deficits and sphingosine-1-phosphate (S1P) - pathophysiology and therapeutic significance
Human Cognitive and Systems Neuroscience
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Vascular dementia is the second most common form of dementia after Alzheimer's disease. The most important known risk factor for the development of vascular dementia or its preliminary stage, the so-called vascular cognitive impairment, is high blood pressure. Apart from lowering blood pressure as a primary preventive measure, there are currently no specific therapies available to treat vascular cognitive deficits. The use of antihypertensive drugs to treat cognitive impairment has thus far yielded contradictory results. A better understanding of the mechanisms underlying the cognitive deficits caused by high blood pressure is therefore urgently needed to identify potential molecular target structures that can be used preventively, but above all therapeutically. Our results support the hypothesis that modulation of a signaling molecule called sphingosine-1-phosphate (S1P), and in particular that of the S1P-generating enzyme (SphK2), represents a potentially effective antihypertensive therapeutic that could also be used to effectively treat hypertension-induced cognitive deficits. In the cerebral microcirculation, S1P acts as a modulator of vascular functions and is therefore of considerable relevance for important regulatory processes of blood vessels, for immune cell interaction with the vascular wall and can influence the regulation of blood flow in the brain. Our work shows that the activation of the S1P-generating enzymes by high blood pressure leads to an increase in S1P levels and thereby has a lasting effect on key brain parameters, such as cerebral blood flow, neuronal health and memory performance. These findings are supported by studies showing a striking association between S1P concentrations and neuronal cell death and a possible role of S1P signaling in learning processes. It can therefore be assumed that any disturbance of the S1P homeostasis confers potential negative effects on important brain structures (e.g., nerve cells, blood vessels) and can ultimately adversely affect brain health and memory performance. Our results have contributed to a better understanding of the role of S1P in hypertension and associated deficits in memory performance. In particular, we have investigated tissuespecific effects of S1P and changes in tissue S1P concentrations in disorders with impaired memory and identified potential new therapeutic targets.
Publications
- Sphingosine-1-phosphate receptor (S1PR) signaling in blood pressure regulation – is S1PR1 doing the trick? Hypertension. 2017: Aug 70 (2), 232-234
A Meissner
(See online at https://doi.org/10.1161/hypertensionaha.117.09200) - The emerging alliance of sphingosine-1-phosphate signaling and immune cells: from basic mechanisms to implications in hypertension. Br J Pharmacol. 2018 Jun 1
Don-Doncow N, Zhang Y, Matuskova H and Meissner A
(See online at https://doi.org/10.1111/bph.14381) - T-cell accumulation in the hypertensive brain: a role for sphingosine-1-phosphate-mediated chemotaxis. Int J Mol Sci. 2019 Jan 28;20(3)
Don-Doncow N, Vanherle L, Zhang Y & Meissner A
(See online at https://doi.org/10.3390/ijms20030537) - Improving cerebrovascular function to increase neuronal recovery in neurodegeneration associated to cardiovascular disease. Front Dev Cell Biol. 2020
Vanherle L, Matuskova H, Don-Doncow N, Uhl FE & Meissner A
(See online at https://doi.org/10.3389/fcell.2020.00053) - An improved method for Physical Separation of Cerebral Vasculature and parenchyma enables detection of blood-brain-barrier dysfunction. Neurosci 2021 Feb; 2 (1)
Matthes F, Matuskova H, Arkelius K, Ansar S, Lundgaard I & Meissner, A
(See online at https://doi.org/10.3390/neurosci2010004) - Plasma S1P links to hypertension and biomarkers of inflammation and cardiovascular disease – findings from a translational investigation. Hypertension 2021. May 17 (78):195-209
Amra Jujic, Frank Matthes, Lotte Vanherle, Henning Petzka, Marju Orho-Mellander, Peter M Nilsson, Martin Magnusson & Anja Meissner
(See online at https://doi.org/10.1161/hypertensionaha.120.17379) - Simvastatin Therapy Attenuates Memory Deficits that Associate with Brain Monocyte Infiltration in Chronic Hypercholesterolemia. NPJ Ageing and Mechan Dis 7, 19 2021
Don-Doncow N, Vanherle L, Matthes F, Matuskova H, Rattik S, Kragh Peterssen S, Härtlova A & Meissner A
(See online at https://doi.org/10.1038/s41514-021-00071-w)
