The role of the PDGF-BB/PDGFR-β signaling pathway in microcirculatory disturbances and BBB destruction after experimental subarachnoid hemorrhage in mice

Abstract

Large vessel spasm after aneurysmal subarachnoid hemorrhage (aSAH) does not fully explain the mechanism underlying delayed cerebral ischemia (DCI), and increasing evidence suggests that microcirculatory function plays an important role in DCI. Previous studies on PDGF-BB and its downstream pathways have focused mostly on large vessel spasms after SAH, and no attention has been given to the relationship between the PDGF pathway and microcirculation. By establishing in vitro and ex vivo mouse SAH models via the addition of PDGF-BB and PDGFRβ antagonists, the expression of PDGFRβ and its downstream proteins was examined to assess the effects of the intervention on neurological function scores, cerebral edema, and blood–brain barrier permeability in mice after aSAH and to observe the state of the cerebral cortex microvasculature in each group of mice after model establishment using transmission electron microscopy. PDGFRβ expression increased after SAH and activated the downstream ERK and AKT pathways, and the inhibitor imatinib inhibited this effect. Imatinib administration ameliorated neurological impairments, reduced brain edema and significantly inhibited blood–brain barrier disruption in mice after SAH. One week after SAH, we observed that imatinib intervention attenuated damage to the microcirculatory system and partially preserved the normal function of the microcirculation. Imatinib reduced BBB disruption and improved microcirculatory function in the early post-SAH period by blocking PDGFR and its downstream pathway, thereby attenuating neurological impairment after SAH. The PDGF-BB–PDGFR-β pathway may play an important role in post-SAH DCI.