This application directly addresses the Broad Challenge Area (13): Smart Biomaterials-Theranostics, and the Specific Challenge Topic: Methods to Evaluate the Health and Safety of Nanomaterials. We are a uniquely qualified laboratory to address this Challenge in that we regularly aerosolize diverse nanoparticles. Concurrently, we are the only laboratory in this area/topic to directly evaluate microvascular health after inhalation exposure to such nanoparticles. This is a critical consideration as the microcirculation is the principal site of origin for numerous vascular pathologies. Given the known health outcomes (cardiovascular morbidity and mortality) from exposure to larger particles and the considerably dynamic nature of nanotechnology, identifying the health effects of nanoparticle exposure may prove far more challenging. This is further confounded by the fact that current methods to evaluate the health effects of exposure to nanomaterials are either not well developed or improperly characterize target systems. This barrier can be overcome, and if the true potential of nanotechnology is to be fully realized, the health effects of nanoparticle exposure must first be clearly defined. Previous work by our laboratory indicates that microvascular function is profoundly impaired after nanoparticle exposure. This impairment is characterized by altered microvascular reactivity and inflammation. We have also characterized age-dependent differences in microvascular function, that may render the young and elderly more susceptible to nanoparticle exposures. We hypothesize that the intensity and duration of systemic microvascular dysfunction that follows pulmonary nanoparticle inhalation is specific to the nanomaterials one is exposed to, and highly dependent on developmental age. To this end, we will define the dose-response and temporal relationships between nanoparticle inhalation and systemic microvascular dysfunction in three distinct age-groups of rats: weanling (25-28 days), juvenile/young adult (42-45 days) and senescent (>1 year). Rats will be exposed to carbon nanotube or nano-titanium dioxide aerosols. After exposure, microvascular reactivity will be studied in skeletal muscle and the coronary microcirculation. Microvascular reactivity will be characterized by responsiveness to endothelium-dependent and -independent vasoactive agents and local inflammation will be characterized by identification of local reactive species, hemoprotein deposition, and nitric oxide bioavailability. Given the opportunity, we will also assess the effect of pre-existing pulmonary inflammation on nanoparticle-dependent microvascular dysfunction. Because nanoparticles interact with the body though non-pulmonary routes, we also propose to evaluate the effect(s) of nanoparticles on skin health and microvascular function. Considering the widespread use of titania based products and carbon nanotubes throughout the U.S., these studies will constitute a critical step in evaluating the vascular health/safety risks of nanoscale products. The biological characterization of microvascular reactivity to diverse nanoparticles is vital to the prevention and treatment of related health effects. This project will determine the microvascular health effects of pulmonary nanoparticle exposure. Rats will be exposed to titanium dioxide nanoparticles and carbon nanotubes via inhalation. Subsequently, intravital microscopy (skeletal muscle) and isolated- cannulated arteriole techniques (subepicardium) will be used to evaluate microvascular reactivity in terms of dose-response, time-course, and the role of aging. PUBLIC HEALTH RELEVANCE: This project will determine the microvascular health effects of pulmonary nanoparticle exposure. Rats will be exposed to titanium dioxide nanoparticles and carbon nanotubes via inhalation. Subsequently, intravital microscopy (skeletal muscle) and isolated-cannulated arteriole techniques (subepicardium) will be used to evaluate microvascular reactivity in terms of dose-response, time-course, and the role of aging.