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<p>The fluid dynamics of blood in the systemic circulation modulates production of nitric oxide (NO), a potent vasodilator. Non-invasive techniques such as the flow-mediated dilation (FMD) test and physiologic phenomena associated with autonomic stress induce hyperemia and subsequently higher levels of wall shear stress (WSS), stimulating endothelial nitric oxide synthase (eNOS) expression. In the current clinical practice, WSS–a key regulator of endothelial function–is commonly estimated assuming a parabolic velocity distribution, despite the evidence that the temporal changes of pulsatile blood flow over the cardiac cycle modulate vasodilation in mammals. This work investigates the effect of cardiovascular stress on local WSS distributions and the potential for near-wall accumulation of nitrite, the vasoactive storage form of NO in the bloodstream. The specific aims of the project are therefore as follows: 1) develop a reduced-order model of the major systemic vasculature at rest, during a flight-or-flight response, and under moderate levels of aerobic exercise; 2) derive a velocity-driven Womersley solution for pulsatile flow to support accurate estimation of pulsatile WSS in the clinical setting; and 3) quantify cumulative transport of nitrite in a multiscale model of bifurcating vasculature utilizing computational fluid dynamics (CFD). Development of these open-source, translatable methods enable accurate quantification of hemodynamics and species transport during cardiovascular stress. Results detailed herein extend our knowledge about regulation of regional blood flow during autonomic stress, suggest a convergent evolutionary theory for having a complete circle of Willis, and potentially clarify reproducibility concerns associated with the FMD test. </p>

To survive, animals must adapt to a complex and challenging world in a way that is flexible and responsive, while maintaining internal homeostasis. Neuromodulators provide a means to systemically alter behavioral or physiological state based on intrinsic or extrinsic cues, however dysregulated neuroendocrine signaling has negative consequences for fitness and survival. Here I examine neuroendocrine function and dysfunction using the escape response in Caenorhabditis elegans. The RFamide neuropeptide FLP-18 is a co-transmitter with the monoamine tyramine and functions both synergistically and antagonistically to tyramine in coordinating escape behavior. Using behavioral analysis and calcium imaging, I show that FLP-18 functions primarily through the G-protein coupled receptor (GPCR) NPR-5 to increase calcium levels in muscle, enhancing locomotion rate, bending and reversal behavior during the escape response. Furthermore, I examine the relationship between persistent acute stress and resilience using repeated activation of the escape response as a model of neuroendocrine dysregulation. Repeated activation of the escape response shortens lifespan and renders animals more susceptible to thermal, oxidative, and nutritional stress. Tyramine release is necessary and sufficient for this effect and activity of the tyraminergic RIM neurons is differentially regulated by acute versus long-term stressors. Impaired stress resistance requires both the GPCR TYRA-3 in the intestine and intestinal neuropeptide release. Activation of the insulin receptor DAF-2 is downstream of TYRA-3 and inhibits the transcription factors DAF-16/FOXO, SKN-1/Nrf2 and HSF-1, linking monoamine signaling in acute stress to the insulin signaling pathway and impaired resilience to long-term stressors.