Role of uroguanylin's signalling pathway in the development of ischaemic stroke

Stroke is one of the leading causes of mortality and disability worldwide. By affecting bradykinin function, activation of guanylate cyclase (GC)‐A has been shown to have a neuroprotective effect after ischaemic stroke, whereas the same has not been confirmed for GC‐B; therefore, we aimed to determine the possible role of GC‐C and its agonist, uroguanylin (UGN), in the development of stroke. In this study, middle cerebral artery occlusion (MCAO) was performed on wild‐type (WT), GC‐C KO and UGN KO mice. MR images were acquired before and 24 h after MCAO. On brain slices 48 h after MCAO, the Ca2+ response to UGN stimulation was recorded. Our results showed that the absence of GC‐C in GC‐C KO mice resulted in the development of smaller ischaemic lesions compared with WT littermates, which is an opposite effect compared with the effects of GC‐A agonists on brain lesions. WT and UGN KO animals showed a stronger Ca2+ response upon UGN stimulation in astrocytes of the peri‐ischaemic cerebral cortex compared with the same cortical region of the unaffected contralateral hemisphere. This stronger activation was not observed in GC‐C KO animals, which may be the reason for smaller lesion development in GC‐C KO mice. The reason why GC‐C might affect Ca2+ signalling in peri‐ischaemic astrocytes is that GC‐C is expressed in these cells after MCAO, whereas under normoxic conditions, it is expressed mainly in cortical neurons. Stronger activation of the Ca2+‐dependent signalling pathway could lead to the stronger activation of the Na+/H+ exchanger, tissue acidification and neuronal death. GC‐C KO animals have smaller ischaemic lesion volume compared with WT littermates. The increase in Ca2+ concentration upon UGN stimulation is higher in peri‐ischaemic astrocytes compared with the astrocytes of the same cortical region in the contralateral hemisphere of WT and UGN KO animals, but not GC‐C KO animals. Under ischaemic conditions, peri‐ischaemic cortical astrocytes express GC‐C, which is not the case for astrocytes in the contralateral hemisphere.