Inflammatory Mechanisms in Arterioles and Venules

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DESCRIPTION (provided by applicant): Acute inflammation is typified by two principal responses in microvessels: 1) an increase in leukocyte-endothelial cell (EC) interactions culminating in leukocyte emigration from the vascular lumen; and 2) increased permeability of the microvascular wall to solutes and water, resulting in tissue edema. Neutrophil interactions with the vessel wall are central to the cascade of events that occurs in inflammation to ultimately result in the alteration in microvascular barrier function, and have been implicated in initiation of solute permeability changes. The overall goal of the studies proposed in this application is therefore to test the general hypothesis that mechanisms underlying inflammatory responses in arterioles and venules are fundamentally different, both with respect to the role of leukocytes in regulation of solute permeability changes, and with respect to whether these two critical aspects of vascular barrier function share essential common signaling mechanisms (specifically those that are Ca2+ dependent). The general goal will be approached in intact arterioles and venules of rodent skeletal muscle, by undertaking the following aims. We will use direct measurements of leukocyte-EC interactions, permeability and EC Ca2+ changes in intact, autoperfused in situ rodent (mice, rats) skeletal muscle arterioles and venules, to define the mechanisms for neutrophil activation of permeability changes, and determine how these differ in arterioles vs. venules. Hypothesis 1: ICAM-1 ligation is sufficient to increase solute permeability and to induce leukocyte diapedesis in both arterioles and venules. Hypothesis 1A: Microvessel permeability to solutes and leukocytes can be increased above that due to ICAM-1 ligation alone by a paracrine product (CAP37) release from neutrophils. Hypothesis 2: An increase in EC Ca2+ is sufficient to increase solute permeability and to induce leukocyte diapedesis in both arterioles and venules. Hypothesis 2A: Both Selectin and ICAM-1 ligation are associated with increased EC Ca2+ and with increased permeability. The study of both skeletal muscle microvasculatures under the same conditions will enable the major mechanisms and important general principles governing regulation of barrier function to be identified in a single, well defined intact vessel model. Understanding mechanisms for regulation of microvascular barrier function, and their potential variation between arteriolar and venular system is of immediate relevance to understanding the progress of inflammatory diseases.