Ocular Vasculogenesis and Angiogenesis Laboratory (OVAL)
Dr. Gerard Lutty is the director of the Ocular Vasculogenesis and Angiogenesis Laboratory (OVAL) at the Wilmer Institute. This laboratory focuses on the retinal and choroidal vasculature and why they become occluded or blocked in diseases like sickle cell and diabetic retinopathy. Dr. Lutty and Scott McLeod have developed techniques to visualize the retinal and choroidal vasculature in dual perspective: vascular pattern in one dimension (Figures 1 & 2) and vascular structure in the second perspective. Using these techniques and immunohistochemistry, the causes of vascular occlusion have been elaborated in diabetic retina and choroid as well as in sickle cell retina and choroid.
|Figure 1. Alkaline phosphatase reaction product in choroidal capillaries in a postmortem human eye shows the vascular pattern of the choriocapillaris. The image has been pseudocolored. The tissue is embedded in a transparent polymer so that blood vessels of interest can be histologically sectioned and the vascular structure determined.|
|Figure 2. Adenosine diphosphatase activity (ADPase) in a preretinal neovascularization formation (called a sea fan formation) from a human postmortem eye of a subject with sickle cell anemia. The image has been pseudocolored. This flat perspective view permits vascular pattern to be determined and then blood vessels of interest can be histologically sectioned.|
This lab has demonstrated that vaso-occlusions occur in the diabetic choroid as well as retina. Recently, they have demonstrated that endothelial cell/ leukocyte adhesion molecules are upregulated in the diabetic choroid and retina. This observation, in addition to documentation of increased numbers of neutrophils (a type of leukocyte that binds to those adhesion molecules) in diabetic choroid and retina which were associated with sites of capillary loss, suggest that neutrophils may contribute vaso-occlusions that occur in diabetic retina and choroid.
The second occlusive retinopathy studied extensively in this lab is sickle cell retinopathy (SCR). Using the dual perspective technique for analysis of the retinal vasculature, they have determined that vaso-occlusions occur in peripheral retina in young children and that the earliest events are mediated by sickled red blood cells (sRBCs). In older individuals with more advanced SCR, leukocytes and fibrin deposition may contribute to the vaso-occlusive process. They have recently developed a rat model to study the mechanism of sRBC occlusion of retinal vessels. The lab has also identified two transgenic mouse models of sickle cell disease that get retinopathy and choroidal neovascularization similar to human subjects with proliferative SCR. These mouse models are exciting forums in which to investigate drugs that might inhibit sRBC sickling as well as neovascularization (Fig. 3).
|Figure 3. Pseudocolor image of sickle erythrocytes (RBCs) from a transgenic mouse who was expressing the sickle beta globin gene, the globin mutation present in subjects with sickle cell anemia. Transgenic mice expressing this gene have retinal and choroidal neovascularization similar to human sickle cell subjects.|
Other studies in OVAL focus on the substances that stimulate new blood vessel growth (neovascularization) after the blood vessels have become occluded. The lab has demonstrated that two angiogenic factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), are elevated in diabetic retinal vessels and, therefore, may contribute to the neovascularization that occurs. They have also performed detailed analysis of the unusual neovascular formations in sickle cell retinopathy and determined that both bFGF and VEGF may stimulate their formation.
The final area of interest in OVAL is development of the retinal vasculature and how exposure of this system to high oxygen results in a retinopathy similar to human retinopathy of prematurity (ROP). Using the canine model of oxygen-induced retinopathy, the lab has demonstrated that retinal vessels develop by vasculogenesis, organization and differentiation of precursors. If neonatal dog is exposed to hyperoxia, vascular development ceases (vaso-obliteration) and eventually neovascularization occurs (vasoproliferation). Both stages in the dog are very similar to human ROP. Recently they have shown that adenosine may mediate both vasculogenesis and neovascularization. Using cells from the dog retinal vessels they have demonstrated that adenosine stimulates both migration of endothelial cells and formation tubes (in vitro blood vessels), both processes that occur in vasculogenesis. Other groups have demonstrated that adenosine may upregulate VEGF production as well.