Piezo1 proteins: Integration of mechanotransduction in microvascular blood flow regulation.

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BACKGROUND: The long-term objective of our basic vascular research program is to understand the mechanisms controlling how blood is delivered to our muscle cells at rest and during exercise. Recently, scientists have discovered a protein that exists in the blood vessels of mammals (e.g., humans and mice) called Piezo1. This protein has the unique ability to sense blood pressure and blood flow. We are interested in discovering how Piezo1 proteins coordinate with other vascular control systems to deliver blood to our muscles. Since males and females have been shown to regulate blood pressure and blood flow differently, we will study Piezo1 proteins in both sexes. OBJECTIVES: 1) Generate and genotype a colony of genetically modified male and female mice which lack Piezo1 proteins in their blood vessels. 2) Systematically determine the hemodynamic roles of Piezo1 channels under baseline conditions. 3) Systematically determine how Piezo1 channels interact with other vascular control systems and blood flow distribution at rest and during contraction. APPROACH: We have developed a means to directly observe the skeletal muscle blood vessels in live mice (using a microscope). We will take videos of these blood vessels and red blood cells at all levels of microvascular networks, under resting conditions, and with drugs and experimental methods that constrict and relax vessels. The data collected will be analyzed for vascular responses in the context of network blood pressure and flow. IMPACT: The integrated nature of experiments in this proposal will provide rigorous, high-quality training for future scientists. We will be first to 1) investigate and describe how flow and pressure in blood vessels are "tuned" to vascular regulation, and 2) how this integration optimizes blood flow in networks that vary in geometry and layout.