Impact of heme and heme degradations products on cerebral vascular reactibility

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Delayed cerebral vasospasm and brain ischemia are the most common causes of mortality and severe neurological impairment in patients with subarachnoid hemorrhage. Options for prevention and medical treatment are still insufficient. Heme and heme degradation products (HHDPs) are involved in the development of vasospasm. As also analyzed in detail in own experiments, especially bilirubin oxidation end products (BOXes), originating from degraded hemoglobin around ruptured blood vessels, induce cerebral vasospasm by inhibiting large conductance BKCa potassium channels in vascular smooth muscle cells. Translation of these results into new treatment strategies requires answers to the following questions: (i) What are the molecular targets of the HHDPs (and specifically BOXes) in cerebral blood vessels, and how can the action be antagonized? (ii) Is delayed cerebral ischemia due to disturbance of capillary blood flow? (iii) Can the in vitro observations be transferred to the in vivo situation, and especially the situation in human patients?In the proposed project, we will identify and characterize the molecular targets of HHDPs in brain vessels and investigate the basis for differential sensitivity in different animals combining wire myography with expression analysis of subunits and splice variants of the BKCa channel. In a second step, we will analyze the role of capillary disturbances for secondary brain ischemia in vitro, and quantify the impact of HHDPs on the vascular reactivity of mouse cerebral blood vessels in vivo. Using high resolution Magnetic Resonance Imaging (9.4 T MRI), we will identify the contribution of pial and/or penetrating resistance arterioles as well as large vessels to HHDP mediated ischemic insults. Applying 2-photon imaging of identified arterioles and capillaries in vivo, we will refine our analysis to the modulatory effect of pericytes, the main regulatory unit for capillary blood flow. In a translational approach we will initiate a transfer of knowledge to patients suffering from subarachnoid hemorrhage. We will investigate the correlation between BOXes and other HHDPs in the cerebrospinal fluid of patients and vasospasm or secondary ischemia and elaborate the parameters for a comprehensive clinical study. The proposed investigations will contribute to the development of innovative treatment strategies in patients with subarachnoid hemorrhage.