Angiogenic Imbalance in Diabetes
The loss of glucose homeostasis in diabetes profoundly impacts every organ in the human body, especially the cardiovascular system. Patients living with Type I and Type II diabetes have greatly elevated risks of heart disease, stroke, and dyslipidemia, as well as dysfunction in the capillary microcirculation, leading to kidney failure, visual impairments, peripheral neuropathy, and impairments in wound healing that directly precede lower limb amputations. Abnormalities in angiogenesis, the growth of new vasculature from pre-existing blood vessels, underlie the progression of these microvascular pathologies. Intriguingly, whereas the late stages of diabetic retinopathy are defined by florid capillary overgrowth in the back of the eye, chronic wounds affecting the extremities, such as diabetic foot ulcers, are hallmarked by the inability of new blood vessels to form in response to cutaneous injuries. Despite the current World Health Organization estimate that nearly 350 million people worldwide are living with diabetes – a figure that is expected to at least double in the next 20 years – few effective treatments are available for individuals experiencing these conditions. Hence, there is a critical need for safe and effective therapeutics for diabetic microangiopathies.
Tony Sheets, an MD-PhD student in the Cellular & Molecular Physiology Program studying Ira Herman, is working on projects aimed at creating next-generation cellular and molecular medicines to quell pathologic neovascularization in proliferative diabetic retinopathy, and to foster wound-healing angiogenesis in chronic diabetic ulcers. Among other factors, extracellular matrix remodeling and cytokines released from activated platelets have been implicated in angiogenesis and other elements of the healing response. Indeed, recent studies from the Herman lab have demonstrated that novel bioactive peptides derived from collagenase-treated extracellular matrices and platelet-rich plasma strongly induce new blood vessel formation and wound closure in several pre-clinical and murine models of impaired healing. Based on these exciting results, Tony is actively investigating whether these peptides improve the healing responses in a porcine model of chronic diabetic ulcers, taking advantage of the many similarities between pig and human skin. In addition, he is studying their mechanisms of action, which may reveal promising new therapeutic targets for stimulating or inhibiting vascular growth.
Tony is also conducting experiments focused on understanding the molecular and cellular machinery that drives vascular overgrowth in proliferative diabetic retinopathy. The loss of pericytes from the retinal microcirculation, which confer stability to capillary networks, has long been suggested as a precipitating factor in aberrant retinal neovascularization. However, the Herman lab has recently revealed that perturbations in pericyte cytoskeletal signal transduction may represent some of the earliest events that contribute to pathological angiogenic activation. Effectively, alterations in pericyte-derived mechanical forces reactivate angiogenic programs within directly contacted endothelial cells, allowing them to re-enter the cell cycle and proliferate. These paradigm-shifting data suggest that contraction-driven changes in endothelial-pericyte communication represent an “angiogenic switch,” culminating in background and proliferative diabetic retinopathy. As the Herman lab has demonstrated the importance of RhoGTPase in pericyte cytoskeletal organization, mechanotransduction, and resultant endothelial cell proliferation, Tony’s studies are centered on elucidating the roles of the RhoGTPase effectors, LIM-kinases and the actin-depolymerizing factor, cofilin, in pericyte-endothelial interactions in angiogenesis. Through these investigations, Tony and the other members of the Herman lab hope to understand the cellular determinants controlling microvascular growth and remodeling, with the long-term goal of creating advanced cellular therapies capable of fostering or restricting angiogenesis, in a disease- and patient-specific context.