Cerebral infarction (stroke) in sickle cell disease (SCD) is one of the most dramatic and life altering complications of the disease, resulting in physical limitations and potential learning disabilities. Evidence suggests that aberrant leukocyte-endothelial interactions and vascular remodeling might be important contributors to the pathobiology of cerebral vasculopathy and stroke in SCD. Our overall goal is to define the potential role of leukocyte- endothelial adhesion and vascular remodeling in the pathobiological mechanism of cerebral vasculopathy and cerebral infarct in SCD. Identifying molecules with significant role in these pathobiological mechanisms could provide a potentially novel drug target for stroke prevention. In our preliminary data we combined two photon laser scanning microscopy (TPLSM) and MRI/MRA in 12 months old Townes humanized sickle cell mice. This approach enabled us to conduct in vivo imaging documenting the occurrence of abnormal vasodynamic measures (higher RBC velocity and flux), cerebral vasculopathy (vessel tortuosity), and cerebral infarcts in sickle cell compared to control mice. Because our outcomes were spontaneously developing, we are poised to be able to determine the potential factors such as leukocyte-endothelial adhesion and/or aberrant angiogenesis that could be driving the evolution of cerebral vasculopathy and infarction. Our hypothesis is that the spontaneous onset and propagation of cerebral vasculopathy in SCD is due in part to aberrant leukocyte-endothelial interaction and vascular remodeling, mediated by increased endothelial activation and a proangiogenic milieu. Sickle cell mice with genetic or pharmacologic blockade of mediators of leukocyte-endothelial interaction and angiogenesis will be generated and used. These mice will be prospectively imaged alongside appropriate controls using the combination of TPLSM and MRI/MRA for development of cerebral vasculopathy and infarcts.
Our specific aims are 1) To determine the spatio-temporal relationship between the presence and/or location of cerebral vasculopathy and incidence, size and number of cerebral infarcts in SCD. This will enable us further validate our model and potentially establish the age of onset for cerebral vasculopathy and infarct in sickle mice. 2) To determine the role of aberrant leukocyte-endothelial interaction in the onset and progression of cerebral vasculopathy and cerebral infarcts. This will allow us to determine whether adhesion molecules already well documented to be associated with known SCD vascular complications are contributors to the pathobiology of cerebral vasculopathy or infarcts and could be potential targets of stroke prevention. 3) To determine the role of vascular endothelial growth factor receptor 2 (VEGFR2) and placenta growth factor (PlGF) in cerebral vascular remodeling, vasculopathy and stroke in SCD. Here we will determine the involvement of angiogenic molecules in the pathobiology of cerebral vasculopathy or infarct in SCD. Also to show whether blocking signaling from these molecules a useful strategy for stroke prevention. Achieving these aims will significantly advance our knowledge of the mechanisms of stroke in SCD.

Public Health Relevance

Brain blood vessel abnormalities, strokes and silent strokes in sickle cell disease (SCD) are still a major source of complications and public health burden due because of their attendant physical and financial consequences. The factors that contribute to the onset and progression of these brain and brain blood vessel abnormalities in SCD is still largely unknown. The aim of this project is to identify some of these factors playing key role and potentially advance our understanding of their role in the development of brain blood vessel abnormalities and stroke in children with SCD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Lerner, Norma B
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Emory University
Schools of Medicine
United States
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Hyacinth, Hyacinth I; Carty, Cara L; Seals, Samantha R et al. (2018) Association of Sickle Cell Trait With Ischemic Stroke Among African Americans: A Meta-analysis. JAMA Neurol 75:802-807
Hartmann, David A; Hyacinth, Hyacinth I; Liao, Francesca-Fang et al. (2018) Does pathology of small venules contribute to cerebral microinfarcts and dementia? J Neurochem 144:517-526
GutiƩrrez, Orlando M; Irvin, Marguerite R; Chaudhary, Ninad S et al. (2018) APOL1 Nephropathy Risk Variants and Incident Cardiovascular Disease Events in Community-Dwelling Black Adults. Circ Genom Precis Med 11:e002098
Shih, Andy Y; Hyacinth, Hyacinth I; Hartmann, David A et al. (2018) Rodent Models of Cerebral Microinfarct and Microhemorrhage. Stroke 49:803-810
Malik, Rainer (see original citation for additional authors) (2018) Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet 50:524-537
Hyacinth, Hyacinth I; Sugihara, Courtney L; Spencer, Thomas L et al. (2017) Higher prevalence of spontaneous cerebral vasculopathy and cerebral infarcts in a mouse model of sickle cell disease. J Cereb Blood Flow Metab :271678X17732275
Wright, Racquel J; Lee, Ken S; Hyacinth, Hyacinth I et al. (2017) An Investigation of the Antioxidant Capacity in Extracts from Moringa oleifera Plants Grown in Jamaica. Plants (Basel) 6:
Coleman, Elisheva R; Moudgal, Rohitha; Lang, Kathryn et al. (2017) Early Rehabilitation After Stroke: a Narrative Review. Curr Atheroscler Rep 19:59
Yilgwan, Christopher S; Hyacinth, Hyacinth I; Oguche, Stephen (2011) Factors associated with decreased survival from neonatal malaria infection in Jos, North Central Nigeria. Niger J Med 20:349-54