We have studied for many years diabetic retinopathy, with the goal of developing preventative strategies. Recent findings and considerations in the context of those studies have led us to a novel hypothesis that reaches beyond diabetic retinopathy, to the fundamental physiology of the microvasculature and of repair systems. The hypothesis states that there are dedicated systems for the surveillance, protection, repair, and healing of adult microvessels, and that the lead system is the "patroller" monocyte. Patroller monocytes are a discrete subset of circulating monocytes that patrol healthy vessels in the absence of any inflammation by "crawling" on the endothelium at a speed that is orders of magnitude lower than rolling. In the steady state, patrollers very rarely extravasate;but in the presence of tissue damage exert healing functions via the secretion of pro-angiogenic and anti-inflammatory cytokines. We see these cells as strong candidates for delivering protective and healing interventions to the cells of blood vessels in the context of their patrolling activity;an we see their defective function as a mechanism that contributes to vascular pathologies. This project aims to test the hypothesis in retinal microvessels. The long life of the retinal capillary cells despite iterative trauma due to the passage of the large blood cells, and the latency with which the vascular lesions of diabetic retinopathy develop, suggest that retinal vessels benefit routinely from the activity of protection and repair systems. The studies will take advantage of a mouse model in which the crawling activity of monocytes is severely impaired by deficiency of the CX3CR1 receptor.
The specific aims of the project are: (1) Test if the impaired crawling on the endothelium and patrolling of vessels documented to occur when monocytes lack the CX3CR1 receptor, accelerates the retinal capillary changes observed in healthy aging;(2) Test if the impaired crawling on the endothelium and patrolling of vessels documented to occur when monocytes lack the CX3CR1 receptor, accelerates the retinal capillary damage induced by diabetes;(3) Test the relation of patroller monocytes to the phenomenon of retinal leukostasis observed after a few weeks of experimental diabetes. Knowing that a discrete subset of circulating monocytes is capable of protecting microvessels against the challenges caused by aging and diabetes would open a new chapter in the understanding and monitoring of vascular physiopathology and in the development of interventions to maintain vascular health.
A conspicuous portion of the pathologies of aging and many manifestations of the complications of diabetes are consequences of dysfunction or damage of smaller vessels and capillaries. This project aims to identify whether there are systems that are dedicated to the protection and repair of the small vessels, how they function, and how they fail. The results could lead to a new understanding of the homeostasis, aging, and pathology of the microcirculation, and could foster the development of new classes of therapeutic interventions that target the maintenance and restoration of microvascular health.