Role of Capillary Stiffness in Diabetic Retinopathy
Diabetic retinopathy (DR) is an important microvascular complication of diabetes and the leading cause of blindness in the working-age population. Growing evidence indicates that DR is a multifactorial condition that is strongly regulated by retinal inflammation. A critical early step in diabetic retinal inflammation is the activation of retinal capillary endothelial cells (ECs). Studies aimed at understanding diabetic retinal EC activation have focused primarily on the role of abnormal epigenetic, metabolic, and inflammatory factors. Our studies are the first to reveal that diabetes leads to significant increase in retinal capillary stiffness that, in turn, contributes actively to retinal endothelial activation. Work is currently underway to decipher the underlying vascular signaling pathways that convert the stiffness-dependent mechanical cues into intracellular biochemical responses in retinal vessels. By uncovering the previously unknown link between vascular stiffening and retinal inflammation, this research will not only illuminate a previously unexplored territory in DR research but, crucially, identify potentially new therapeutic targets for superior management of DR.
Micromechanical Control of AMD Pathogenesis
Age-related macular degeneration (AMD) commonly causes blindness in the elderly. Yet, only 10-15% of all AMD patients that develop the advanced ‘wet’ stage benefit from current therapies while no therapies exist for the more prevalent ‘dry’ form. Thus, there is an unmet need to better understand and treat dry AMD. Our lab is taking a unique multidisciplinary approach to understand the role of age-related vascular stiffening in the pathogenesis of dry AMD, with an emphasis on examining the micromechanical control of choriocapillaris atrophy that is implicated in retinal tissue degeneration. This research, which is being performed in collaboration with the Oregon Health and Science University, involves the use of a rhesus macaque model of dry AMD. Rhesus monkeys are a unique model for the study of dry AMD because unlike non-primate models, they (a) have a retinal structure closely resembling that found in humans, (b) share the same AMD susceptibility genes ARMS2 and HTRA1 with humans, and (c) undergo drusen accumulation as seen in humans. Thus, the use of rhesus macaques in these studies will ensure that their findings are readily applicable towards the understanding of AMD in humans.
This research is currently being funded by an AMD grant from BrightFocus Foundation.
Mechanobiology of Cardiovascular Inflammation
Vascular inflammation is a hallmark of diabetic cardiovascular complications such as atherosclerosis. These conditions involve an increase in the stiffness of aortas and arteries, which are the major vessels that are commonly affected by inflammation. Our lab is trying to better understand how the increased stiffness of the aorta contributes to leukocyte binding to the aortic endothelial cells (ECs), which marks the earliest step in cardiovascular inflammation. So far, their studies have identified a mechanosensitive calcium ion channel as a novel regulator of matrix stiffness-dependent vascular inflammation. We are currently validating these in vitro findings in mouse models of diabetes and atherosclerosis. Simultaneously, we are also identifying and characterizing the upstream regulators of the stiffness-dependent mechanical control of vascular inflammation, with an initial emphasis on the role of epigenetic factors such as microRNAs.
This research was funded by a grant from the City of Hope-UC Riverside Biomedical Research Initiative (CUBRI).
Image: Retinal capillaries of a diabetic mouse stained with Isolectin GS-IB4 and CD68 to label capillary endothelial cells and adherent leukocytes, respectively.
Image: Choriocapillaris of an aging rhesus macaque monkey eye is immunostained for membrane attack complex (MAC; C5b-9), which deposits at sites of complement activation.
Image: Aorta of a diabetic (db/db) mouse immunolabeled for lysyl oxidase (LOX), a major extracellular matrix crosslinking (stiffening) enzyme.