Dr. Hyacinith Awarded RO1 “Mechanism of Cerebral Vaculopahty and Stroke in Sickle Cell Disease”
Project Narrative 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.
Project Abstract 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.