{
  "abstract": "Aneurysmal subarachnoid hemorrhage (SAH) is a devastating form of stroke that affects roughly 30,000 people in the United States every year. Delayed cerebral ischemia (DCI) is the leading treatable cause of poor outcome after aneurysmal SAH, resulting in death or disability in 30% of all SAH patients. Capillary pericytes are contractile cells that line brain capillaries, and their aberrant contraction can lead to impairment of capillary perfusion and overall cerebral blood flow in conditions such as acute, ischemic stroke, and have been implicated in the pathophysiology of DCI. Impairments in microcirculatory perfusion after SAH lead to the formation of microvascular thrombi, which is independently associated with poor neurological outcome. This study examines the mechanism by which capillary pericytes contract and impair microcirculatory perfusion, and demonstrates that the Rho-Kinase inhibitor Fasudil, a vasodilatory agent, can be used as a rescue therapy for this injurious phenomenon.Chronic cranial windows were adhered on mice that were either wild-type or expressing Gq-DREADD, allowing for precise chemogenetic manipulation of capillary pericytes in vivo. Mice were imaged using two-photon microscopy, obtaining baseline imaging of the cerebral microvasculature after after IV injection of 2 MDa fluorescent dextran to label the blood plasma. Detailed morphological and RBC flux assessment was performed, Next, DCZ, a high-affinity selective agonist for Gq-DREADD, was administered to induce contraction of capillary pericytes in the central nervous system. After repeating the analysis of microvascular characteristics, Fasudil was administered. 1h post-administration, repeat assessment was performed. Identical experiments were performed with phosphate-buffered saline administration as a vehicle control.Capillary pericytes in the GqDREADD mouse groups contract in response to DCZ administration, with significant decrease in vessel lumen diameter and RBC flux in comparison to baseline. Fasudil treatment robustly rescues this contractile effect, with significant increases seen in both vessel lumen diameter and RBC flux 1h post-administration in comparison to post-DCZ and vehicle-treated conditions.Fasudil significantly improves central nervous system microcirculatory perfusion and rescues against capillary pericyte contraction. Further investigation into this agent as a novel therapeutic option for prevention of microvascular thrombosis after SAH is warranted.Disclosures J. Clarke: 1; C; American Heart Association, NINDS, Brain Aneurysm Foundation, AANS/CNS Joint Cerebrovascular Section.",
  "authors": [
    {
      "affiliations": [
        "Department of Neurological Surgery, University of Washington, Seattle, WA"
      ],
      "name": "J Clarke"
    }
  ],
  "title": "E-161 Pharmacologic rescue of central nervous system microcirculatory impairment",
  "uid": "66818b46-bfb5-5e50-8fd5-b024bdba3c44"
}