Human tissue kallikrein alleviates microcirculation dysfunction of symptomatic cerebral vasospasm via eNOS upregulation in rabbits

Cerebral microcirculation dysfunction might play an important role in symptomatic cerebral vasospasm (CVS), and this study was to investigate whether human tissue kallikrein (HTK) can alleviate it. In this study, forty-four rabbits were randomly divided into sham-operated, subarachnoid hemorrhage-operated (SAH), SAH+HTK groups and SAH+HTK+L-NNA groups (n = 11/group). Neurological function and food intake were evaluated on the day before and for 7 days after SAH. Three-dimensional computed tomography angiography was used to determine the diameter of the basilar artery. Western blotting and immunohistochemistry were used to determine the expression of hippocampal endothelial nitric oxide synthase (eNOS) and CD34 respectively. Finally, the microvascular area ratio and field microvessel density (MVD) were quantitated. SAH reduced food intake and caused neurological dysfunction, which were countered by HTK administration. HTK also significantly increased the basilar artery diameter and reduced CVS following SAH. The microvascular area ratio and MVD were reduced in the SAH group, which was countered by HTK treatment. Moreover, HTK treatment increased eNOS expression. Moreover, N-nitro-l-arginine(LNNA) prevented the protection of HTK; the L-NNA group showed reduced basilar artery diameter, microvascular area ratio, MVD, and eNOS. During post-SAH symptomatic CVS, capillary numbers and the open area of the microcirculation in the hippocampus declined. HTK improved the microcirculation status of symptomatic CVS and upregulated cerebral perfusion pressure by increasing capillary neogenesis and expanding spasmodic microvessels. HTK may exert its action via upregulation of eNOS, which may cause release of more nitric oxide within the hippocampus.