PROJECT SUMMARY Heart disease is the leading cause of death in the United States. Diaphragm dysfunction is prevalent in heart failure (HF) patients and both precedes and surpasses that seen in other locomotory skeletal muscles; increasing susceptibility to respiratory muscle failure and exercise intolerance as well as predisposing these patients to ventilator-induced diaphragmatic dysfunction (VIDD). Impaired vascular function is regularly present in peripheral skeletal muscles with HF, compromising the blood flow and oxygen delivery required to support contractile function. However, the role of diaphragm vascular dysfunction in HF-induced diaphragm fatigue, and whether these changes in diaphragm vasomotor control are exacerbated with prolonged mechanical ventilation (MV), often employed in this patient population, is not known. Further, cardiovascular dysfunction is an important contributor to problematic weaning and increased mortality with MV. Prolonged MV in-and-of itself elicits diaphragm vascular dysfunction, which contributes to weaning failure with MV. HF and MV patients consistently exhibit increased renin-angiotensin system (RAS) activation and elevated levels of circulating Angiotensin-II (Ang-II), which largely contributes to skeletal muscle vascular dysfunction as well as diaphragm atrophy in both HF and prolonged MV. These findings suggest that HF patients are predisposed to more pronounced MV-induced diaphragm vascular dysfunction. Preliminary data supports that HF impairs endothelial-dependent vasorelaxation in diaphragm arterioles, and the added insult of prolonged MV nearly abolishes endothelial-dependent vasorelaxation. However, the impact of HF combined with prolonged MV on diaphragm blood flow and vasomotor control has never been determined. Therefore, our global hypothesis is that diaphragm resistance vessel (i.e. arterioles) function (e.g. endothelial-dependent vasorelaxation) is significantly diminished in HF and exacerbated with MV. As such, pharmacologically counteracting the vascular effects of Ang-II will improve diaphragm perfusion and preserve vascular function with prolonged MV and HF + prolonged MV. This project will be completed at Kansas State University (KSU) under the guidance of Drs. Bradley J. Behnke and David C. Poole. The training plan has been formulated to facilitate the development of technical proficiencies and critical thinking skills needed to execute the proposed experiments and incorporates the elements essential for the applicant to transition into an independent scientific career. The Behnke and Poole Laboratories, and the Departments of Kinesiology and Anatomy and Physiology at KSU represent a rich scientific environment that will provide outstanding graduate training and a research opportunity to gain new insights into diaphragm blood flow regulation and vasomotor control in healthy and diseased animal models.