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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZHL1-CSR-N (S1))
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Goldman, Stephen
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University of Rochester
Schools of Dentistry
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Sumagin, Ronen; Sarelius, Ingrid H (2013) Emerging understanding of roles for arterioles in inflammation. Microcirculation 20:679-92
Corr, Maripat; Lerman, Irina; Keubel, Julia M et al. (2012) Decreased Krev interaction-trapped 1 expression leads to increased vascular permeability and modifies inflammatory responses in vivo. Arterioscler Thromb Vasc Biol 32:2702-10
Sumagin, Ronen; Kuebel, Julia M; Sarelius, Ingrid H (2011) Leukocyte rolling and adhesion both contribute to regulation of microvascular permeability to albumin via ligation of ICAM-1. Am J Physiol Cell Physiol 301:C804-13
Sumagin, Ronen; Sarelius, Ingrid H (2010) Intercellular adhesion molecule-1 enrichment near tricellular endothelial junctions is preferentially associated with leukocyte transmigration and signals for reorganization of these junctions to accommodate leukocyte passage. J Immunol 184:5242-52
Sumagin, Ronen; Prizant, Hen; Lomakina, Elena et al. (2010) LFA-1 and Mac-1 define characteristically different intralumenal crawling and emigration patterns for monocytes and neutrophils in situ. J Immunol 185:7057-66
Sumagin, Ronen; Lamkin-Kennard, Kathleen A; Sarelius, Ingrid H (2009) A separate role for ICAM-1 and fluid shear in regulating leukocyte interactions with straight regions of venular wall and venular convergences. Microcirculation 16:508-20
Sumagin, Ronen; Lomakina, Elena; Sarelius, Ingrid H (2008) Leukocyte-endothelial cell interactions are linked to vascular permeability via ICAM-1-mediated signaling. Am J Physiol Heart Circ Physiol 295:H969-H977
Huxley, Virginia H; Wang, Jian Jie; Sarelius, Ingrid H (2007) Adaptation of coronary microvascular exchange in arterioles and venules to exercise training and a role for sex in determining permeability responses. Am J Physiol Heart Circ Physiol 293:H1196-205
Sumagin, Ronen; Sarelius, Ingrid H (2007) A role for ICAM-1 in maintenance of leukocyte-endothelial cell rolling interactions in inflamed arterioles. Am J Physiol Heart Circ Physiol 293:H2786-98
Huxley, Virginia H (2007) Sex and the cardiovascular system: the intriguing tale of how women and men regulate cardiovascular function differently. Adv Physiol Educ 31:17-22

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