PlesnilaLab: Laboratory of Experimental Stroke Research
The main interest of the laboratory is to study the role of cerebral vessels for the pathophysiology of acute and chronic brain injury and to use the evolving knowledge for the development of novel therapeutic strategies for patients. For this purpose we use clinically relevant mouse models for acute and chronic brain injury and investigate neuro-vascular morphology and function by in vivo microscopy using conventional and 2-photon fluorescence microscopy.
The work of the Laboratory of Experimental Stroke Research currently focuses around two topics: 1) the role of the cerebral microcirculation for brain injury after subarachnoid hemorrhage (SAH) and 2) the function of cerebral microvessels in physiological and pathological aging. Regarding SAH we discovered that early surgical decompression results in an increased rate of secondary bleedings thereby significantly worsening outcome and that inhaled nitric oxide reduces cerebral microvasospasms by -85% and blunts mortality. Further, we demonstrated that pial and intraparenchymal microvessels show a complete loss of CO2 reactivity after SAH. This finding suggests that SAH induces severe neuro-vascular dysfunction already within the first few hours after brain hemorrhage. Experiments on the aging brain demonstrated that already normal aging results in severe dysfunction of cerebral microvessels. While young vessels dilate and remain dilated upon repetitive neuronal activation, vessels from only eight month old mice dilate less and start to constrict with ongoing neuronal activity. These findings suggest that rather vascular and not necessarily neuronal dysfunction may be responsible for the reduced attention span at older age. Finally, we could demonstrate that the first pathological alteration in a mouse model of CADASIL is the retraction and death of microvascular pericytes. As a consequence the blood brain barrier becomes dysfunctional, plasma proteins enter the brain, and astrocytic end-feed detach from cerebral capillaries. These changes start to occur at an age of 4-8 month and precede white matter damage by more than one year. Accordingly, pericytes may represent the primary target for the cure of CADASIL.Figure (top): CADASIL-associated aggregation of mutated NOTCH3 extracellular domain induces pericyte dysfunction and loss well before white matter damage occurs. As a consequence tight junctions open up, astrocytic end-feet detach from cerebral microvessels, and the blood-brain barrier becomes leaky to neurotoxic plasma components.
Contact: Prof. Dr. med. Nikolaus Plesnila
Sectretary: Hedwig Pietsch