Sickle cell disease is characterized in part by repeated bouts of tissue ischemia due to vascular occlusion. Most of the complications of sickle cell disease including stroke, pain crises, renal failure, etc. can be attributed to these episodes of vascular insufficiency. A normal adaptive response of the human body to vascular occlusion is the development of collateral blood vessels to allow perfusion of the vascular bed distal to the site of obstruction. In other diseases such as coronary artery disease and peripheral vascular disease, dysfunctional collateral blood flow is associated with increased morbidity and mortality. We have hypothesized that in sickle cell disease, formation of dysfunctional collateral blood vessels is directly related to many aspects of the ultimate pathology of the disease. The studies proposed in this application are based on exciting preliminary data generated by the co-PI?s that show that in a murine model of sickle cell disease, collateral vessel formation is dramatically impaired and that a hallmark of the pathology is a maladaptive response to ischemia that results in excessive inflammation and overproduction of reactive oxygen species. We will attempt to gain a greater understanding of dysfunctional collateral vessel formation in sickle cell disease and more importantly, obtain insights into the underlying pathological mechanisms in order to lay the groundwork for novel therapeutic strategies. Our overall hypothesis is that collateral vessel formation in sickle cell disease is impaired as the result of a disproportionate inflammatory response driven by the excessive production of reactive oxygen species.
Sickle cell disease is characterized in part by repeated bouts of tissue ischemia due to vascular occlusion. We have hypothesized that there is a defect in the ability to form functional collateral vessels in sickle cell disease.
| Okwan-Duodu, Derick; Hansen, Laura; Joseph, Giji et al. (2018) Impaired Collateral Vessel Formation in Sickle Cell Disease. Arterioscler Thromb Vasc Biol 38:1125-1133 |
