Grant: Discovery Grants Program - Individual

Background: Resistance arterioles in the body play a critical role in regulating bulk blood flow to, and perfusion distribution within, tissues and organs. In order to do this effectively, they must integrate a myriad of vasomotor stimuli in a manner that allows them to regulate their tone effectively and produce an appropriate outcome. While there has been extensive investigation on the major individual regulators of vascular tone (e.g., myogenic activation, adenosine-induced dilation), there has been comparatively little investigation into how these stimuli are integrated by the arteriole to produce the outcome. Approach: To address this, we will use well-established and validated techniques for studying vascular function, our innovative multi-scale approach to the study of parameter interaction for vascular tone regulation, and the novel approaches developed by our collaborative team to study how resistance arterioles integrate physiologically critical vasoactive stimuli to determine their diameter and reactivity. In order to keep the experimental number manageable, we will focus on the interactions of myogenic activation (intrinsic vascular control), adrenergic control (extrinsic vascular control) and adenosine-induced dilation (parenchymal cell influences). Microvascular networks will be studied using the in situ gluteus maximus muscle preparation, developed and perfected by our collaborator (Jackson), while ex vivo microvessels will be assessed using our well established double-cannulation procedures. If needed, we will also use our established in vivo hindlimb preparation to gain insight into microvascular network and resistance arteriolar behavior via tracer washout kinetics. Integrating all of these results, we will utilize the novel computational approaches developed by our collaborator (Goldman) to identify novel targets for study and vascular relationships that will be targeted in our evolving program.Contribution to HQP Training: In order to maximize the training potential from this projects and the resulting HQP, we will utilize our long-standing approach of immersing our trainees into studies interrogating these relationships at multiple levels of resolution, spanning in situ microvascular networks, ex vivo isolated microvessels, high resolution biomarker and metabolite profiling (for mechanistic insight), with additional training in basic computational approaches to the study of microvascular network behavior.Impact: As our program develops, we will not only gain truly novel insight into how resistance arterioles regulate their tone in a complex environment of fluctuating stimuli, but we will also produce HQP of exceptional quality as they will have been thoroughly trained in the study of microvascular function at multiple levels of spatial resolution spanning metabolite production to in situ and in vivo blood perfused skeletal muscles.