Targeting vascular contractile cells in capillary stasis after cardiac arrest

心脏骤停后毛细血管停滞中靶向血管收缩细胞

• 批准号: 10376256
• 负责人: Mioara D. Manole
• 金额: $ 19.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376256
• 关键词: Address; Anxiety; Apple; Area; Attenuated; Binding; Blood Vessels; Blood capillaries; Brain; Brain Injuries; Breeding; CSPG4 gene; Cardiopulmonary Resuscitation; Cells; Cerebral Hypoxia; Cerebrum; Data; Development; Drug Compounding; Goals; Heart Arrest; Histologic; Hydroxyeicosatetraenoic Acids; Hypoxia; Impairment; Induced Heart Arrest; Intervention; Intravenous; Investigation; Ischemia; Label; Lead; Mediating; Metabolism; Methods; Microcirculation; Modeling; Motor Cortex; Mus; Muscle Contraction; Neurologic; Neurological outcome; Neuronal Injury; Neurons; Outcome; Outcome Assessment; Perfusion; Pericytes; Platelet-Derived Growth Factor beta Receptor; Pre-Clinical Model; Relaxation; Resuscitation; Rodent; Role; Smooth Muscle Myocytes; Survivors; Techniques; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Model; Vascular Smooth Muscle; Vasodilator Agents; Viral; clinically relevant; designer receptors exclusively activated by designer drugs; heart function; high reward; high risk; improved; improved outcome; in vivo; innovation; memory recognition; memory retention; neonatal hypoxic-ischemic brain injury; neurological recovery; neuropathology; neurovascular unit; novel; novel therapeutics; prevent; receptor; spatial memory; targeted treatment; vasoconstriction

ABSTRACT There are more than 500,000 cases of cardiac arrest in the US annually. While timely resuscitation is often effective at restoring cardiac function, many survivors develop brain injury. After resuscitation from cardiac arrest, cerebral microvascular disturbances produce a secondary neuronal injury that worsens neurological outcome. We have recently uncovered important cortical microvascular alterations in a clinically relevant model of asphyxial cardiac arrest: multifocal capillary stasis in cortical capillaries and arteriolar vasoconstriction. Preliminary data also suggest that pericytes and smooth muscle cells contribute to capillary stasis. Moreover, a microvascular-targeted strategy partially improved cortical perfusion and neurological outcome in our model. To fully elucidate the role of vascular contractile cells in capillary stasis and neurological outcome, we propose to use a highly specific chemogenetic approach in a model of asphyxial cardiac arrest in mice. Using viral transduction, we will induce the expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADD) in pericytes in PDGFRβ-CreER mice, and in both pericytes and smooth muscle cells in NG2- CreER mice. Activation of inhibitory DREADDs will induce relaxation of pericytes and smooth muscle cells after cardiac arrest. Aim 1 will define the full scope of the effect of pericyte and smooth muscle cells relaxation on cardiac arrest-induced capillary stasis in mice expressing the inhibitory hM4Di chemogenetic receptor. The inhibitory DREADD AAV-EF1a-DIO-hM4D(Gi)-mCherry will be injected in the motor cortex of PDGFRβ-CreER and NG2-CreER mice. We will assess the isolated effect of pericyte relaxation and the combined effect of pericyte and arteriolar smooth muscle cells relaxation on capillary perfusion. Aim 2 will determine if inducing relaxation of pericytes post-cardiac arrest improves neurological and histological outcomes. For this aim, we will express the inhibitory DREADD hM4Di in all pericytes by breeding PDGFRβ mice with R26-LSL- hM4Di/mCitrine mice. We will induce cerebral and then global pericyte relaxation after cardiac arrest and assess neurological and histological outcomes. Through this novel and specific approach, we will characterize the role of pericytes and smooth muscle cells in mediating microvascular stasis after cardiac arrest. If successful in improving neurological outcome, this microvascular targeted strategy could lead to a novel therapeutic opportunity to prevent secondary brain injury.

摘要