The endothelial lining produces key substances such as nitric oxide (NO) for the maintenance of vascular homeostasis. Cardiovascular diseases affecting the heart (coronary artery disease) and skeletal muscle (peripheral artery disease) can be attributed to a pathological transformation of the endothelium from a NO producing cell which is vasoactive, antithrombotic, and regenerative; to a cell which exhibits impaired vasodilation, increased thrombus formation, and a lost capacity for cellular repair because NO production is inhibited. Cardiovascular risk factors such as age, hypertension, hyperlipidemia, PTSD and tobacco use induce inflammatory signals which stimulate this pathological transformation. One manifestation of endothelial dysfunction is the chronic ulcerative wounds seen in patients with diabetes and peripheral artery disease. Our nation's veterans are at high risk for chronic ulcerated wounds because they possess many of these cardiac risk factors. This Veterans Administration Career Development Award (CDA-2) is conceived on the premise that light energy produces a novel means for increasing NO which is scavenged by endothelial dysfunction, and in the future may lead to the development of novel vascular therapies targeted to improve wound healing. These investigations are directed to test the hypothesis that light energy can release NO specifically to ischemic tissues. This alternative source of NO has the potential to improve endothelial function in regions where NO production is attenuated, thereby improving vessel reactivity and wound healing. Our hypothesis will be tested by targeting a defined set of proteins known to produce and bind NO and measure its production before and after energy exposure. We will also measure the impact of energy to stimulate vasodilation and wound healing under physiological conditions and inflammatory stress. The information gained from this investigation will expand our understanding of where important NO stores in the cell exist, and how energy can stimulate these stores to improve endothelial cell homeostasis in inflammatory disease.
Effective treatments for chronic ulcerative wounds are limited, thus leaving patients with chronic pain and possible amputation. Trials using red light therapy has improved healing of chronic ulcerative wounds, but its broad application is limited by an incomplete understanding of the mechanism by which light acts on cells and tissue. RELEVANCE TO VA POPULATION: The VA has over 227,000 annual visits in the evaluation and treatment of chronic ulcerative wounds. Risk factors for chronic wounds (diabetes, peripheral artery disease active tobacco use) are prevalent in the VA population. Energy has the potential to change the paradigm of health care delivery to reduce costs and improve wound healing. The broader clinical impact of red light therapy cannot be fully realized until the mechanism by which energy increases NO is characterized.
| Keszler, Agnes; Lindemer, Brian; Hogg, Neil et al. (2018) Wavelength-dependence of vasodilation and NO release from S-nitrosothiols and dinitrosyl iron complexes by far red/near infrared light. Arch Biochem Biophys 649:47-52 |
| Lohr, Nicole L (2018) Function over form: Is it time to use endothelial function to diagnose vascular diseases? Int J Cardiol 260:191-192 |
| Keszler, Agnes; Lindemer, Brian; Weihrauch, Dorothee et al. (2017) Red/near infrared light stimulates release of an endothelium dependent vasodilator and rescues vascular dysfunction in a diabetes model. Free Radic Biol Med 113:157-164 |
