The Role of Nitric Oxide Synthase in Circulating Progenitor Cell Function

Investigator: Matthew Springer, PhD
Sponsor: NIH National Heart, Lung, and Blood Institute

Location(s): United States


We propose to determine the role of endothelial nitric oxide synthase (eNOS) in age- or disease-related dysfunction of human endothelial progenitor cells (EPCs). One consequence of aging or accumulating different cardiovascular risk factors is a decrease in the functional capabilities of the vascular endothelium. This appears to correlate with a decrease in EPC function as measured ex vivo. Transplantation of EPCs in both animals and humans has been suggested to enhance functional tissue preservation/regeneration after myocardial infarction or peripheral ischemia, a possibly that is supported by our own preliminary studies. However, EPC function has been shown to determine the extent of tissue recovery. Decreased EPC function in culture is associated with decreased ability of EPCs to aid in tissue regeneration when transplanted after myocardial infarction. This presents the problem that ex vivo expansion and re-infusion of a patient's own EPCs may be ineffective if the EPCs themselves are functionally impaired. The main hypothesis of this proposal is that EPC function is impaired in some populations with high cardiovascular risk as a result of reduced eNOS-dependent nitric oxide (NO) production, and that dysfunctional EPCs can be functionally enhanced by engineering them to overexpress eNOS. The specific aims are (1) to evaluate whether a correlation exists between EPC function and eNOS-dependent NO production in EPCs from populations with high versus low cardiovascular risk, including age, (2) to assess whether engineering EPCs to overexpress eNOS enhances their ability to improve function in rodent models of cardiovascular disease, and (3) to examine the mechanistic role of NO in EPC function. RELEVANCE: Progenitor cells that circulate in the blood are thought to participate in the growth and maintenance of blood vessels. Such progenitor cells from elderly individuals, or people who suffer from certain cardiovascular maladies, are less able to function than those from healthy young individuals. This research will determine if a deficiency in the enzyme eNOS is partially responsible for this problem, and will also explore the possibility of genetically engineering such progenitor cells to improve their function, thereby increasing their beneficial effects.