Cellular and Molecular Physiology of Sympathetic Innervation of Vascular Smooth Muscle

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The goal of my NSERC research program is to understand control of blood pressure and blood flow through the body. Sympathetic nerves surrounding blood vessels cause contraction of vascular smooth muscle cells and reduce vessel diameter; if these nerves are over-active, they can cause high blood pressure, while their under-activity promotes fainting. In contrast to most brain nerve cells, which release one type of neurotransmitter (NT), sympathetic nerves "co-release" multiple NTs. Regulation of transmitter co-release is poorly understood at the molecular level. In the next five years, my NSERC research will explore three fundamental aspects of how sympathetic nerves store and release multiple NTs in order to address long-standing gaps in our understanding of sympathetic regulation of blood vessel diameter. Norepinephrine (NE) and ATP are the main NTs released onto blood vessels. Whether sympathetic nerves store NE and ATP in the same releasable vesicles or separate vesicles has been debated for 30 years. We recently reported compelling evidence that NE and ATP are stored in separate vesicles. In Objective 1, we will use advanced (super-resolution) microscopic and molecular methods to understand the molecular basis of separate NT storage and co-release. This work will clarify how these nerves respond to a wide range of physiological conditions. NT release requires calcium to enter nerve terminals through voltage-gated calcium channels from the CaV2 family. Different forms of these channels can be targeted to specific locations in cells and nerve terminals. Knowing which channels cause the release of one or more types of NT will help us to understand how one set of nerves can release different NTs in different situations. In Objective 2, we will determine which NTs are released by three channels (CaV2.1, CaV2.2 and CaV2.3) in differential vascular beds and cell culture models using novel imaging methods. Mitochondria are organelles best known for making ATP, but they also modulate localized calcium signals. We will study how these mitochondrial functions impact the release of NE and ATP from sympathetic nerves. In Objective 3, we will test if mitochondria differentially affect NE or ATP release, over physiological stimulation frequencies. These studies will improve our understanding of how the loss of mitochondria might affect sympathetic nerve function and smooth muscle regulation in aging blood vessels. The novelty of this research program lies in creatively using modern methods to address decades-old questions about NT co-release. Our research will enrich our knowledge of neural control of blood vessels and will be of immediate use to others studying NT co-release and help identify therapeutic targets for the treatment of hypertension. Researchers studying the brain and hormone secretion will benefit from our genetically encoded reporters, and microscopists will benefit from the image analysis algorithms and software that we create.