Regulation of blood flow in the brain by capillary KATP channels - PROJECT SUMMARY: Approximately 90% of the blood vessels in the brain are capillaries, which have been traditionally viewed solely as a dense and passive network of tiny vessels which allow efficient nutrient and waste exchange. More recently, the capillaries have been appreciated for their ability to sense brain activity/environments and electrically communicate these signals with upstream arteries/arterioles to ensure rapid and efficient blood flow regulation. The initiation and propagation of these hyperpolarzing electrical signals in the capillaries requires activation of vascular potassium ion channels such as inwardly-rectifying K+ 2 channels (Kir2). Recently, the ATP-sensitive K+ channel (KATP) channel has been functionally characterized in capillary endothelial cells (cECs) and pericytes. The physiological stimuli which activate capillary KATP channels and regulate blood flow in the brain are unclear. Furthermore, the electrical signaling and amplification processes between pericytes and cEC are poorly understood. Drops in brain O2 concentration can occur in response to many physiological and pathological conditions such as stroke, tumor growth, altitude change, and hypotension, and consequently results in a metabolic challenge to cells and leads to accumulation of extracellular adenosine. Both changes in cellular ATP and adenosine signaling can stimulate KATP channel function. Here, I hypothesize that local and global hypoxic events stimulate capillary pericyte and cEC KATP channel activity and hyperpolarization, the latter of which is amplified and propagates through cEC Kir2.1 activation to increase blood flow. I will test this hypothesis with two distinct aims. First, I will elucidate the mechanisms by which capillary KATP channels increase cerebral blood flow to hypoxia. Second, I will elucidate electrical coupling and amplification processes within and between capillary pericytes and cECs during KATP activation. These aims will be accomplished using newly developed animal models, electrophysiology in native isolated cells and intact tissues, and advanced optical imaging in isolated tissue and whole animals. Dr. Nicholas Klug has an ideal training history in vascular physiology, an exceptional environment in the laboratory of Dr. Mark Nelson, and a high potential as an independent, NIH funded vascular researcher. Dedicated mentoring from the mentoring committee of Dr. Mark Nelson and Dr. Andy Shih (University of Washington) will provide Dr. Klug with new and expanded knowledge and tools in vascular physiology, optical imaging approaches, and ion channel function and provide detailed professional guidance to distinguish himself as an independent investigator. Collaboration with Dr. Christer Betsholtz and Dr. Yangguang Ou will provide new models and tools to properly address the role of capillary sensing/signaling and adenosine release in vivo. Ultimately, the K01 Award provides substantial structure and support which will place Dr. Klug in a strong position for continuous R01-level support, his research will expand our understanding of the sensing and signaling properties of capillaries within the central nervous system.
