Gap junctions are clusters of intercellular channels, composed of connexin proteins, that connect the cytoplasm of adjacent cells, allowing the direct transfer of small molecules. In the vascular wall, three connexins are expressed (Cx37, Cx40, and Cx43) which may mediate communication among endothelial cells, smooth muscle cells, and between endothelial cells and smooth muscle cells. The long-term goal of this project is to understand the role that gap junction communication plays in regulating vascular responses and to define the contributions of specific connexins. It is thought that vascular communication is an important pathway for coordination of vasomotor responses, by allowing for transfer of electrical and/or chemical signals. Two viable connexin knockout mouse lines (Cx37KO and Cx4OKO mice) and a line deficient in both connexins (Cx37/40K0) were previously generated, allowing a test of the role of specific connexins in vascular communication and function. In this study, intracellular injection of gap junction-permeable tracers is used to track changes in endothelial, myoendothelial, and smooth muscle communication in connexin knockout versus wild-type blood vessels, while whole-cell voltage clamp is performed to compare ionic coupling. The possibility that Cx37 and Cx4O interact to form heteromeric channels is investigated in cell culture by transfection of connexin expression vectors and by single channel recordings. The role that Cx37 and Cx40 play in vasomotor responses is examined by performing isometric tension measurements on wild-type and connexin knockout aortic rings treated with a vasodilator or a vasoconstrictor. The possibility that Cx37 and/or Cx40 contribute to myoendothelial gap junctions and mediate endothelium-dependent, NO-independent relaxation responses is investigated. Because gap junctions may be important in maintaining vascular homeostasis and responsiveness, a better understanding of vascular intercellular communication could lead to new insights and treatments for atherosclerosis, hypertension, and types of angina caused by vasospasm of coronary vessels.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pathology A Study Section (PTHA)
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Goldman, Stephen
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University of Arizona
Schools of Medicine
United States
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Munger, Stephanie J; Davis, Michael J; Simon, Alexander M (2016) Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43. Dev Biol :
Munger, Stephanie J; Geng, Xin; Srinivasan, R Sathish et al. (2016) Segregated Foxc2, NFATc1 and Connexin expression at normal developing venous valves, and Connexin-specific differences in the valve phenotypes of Cx37, Cx43, and Cx47 knockout mice. Dev Biol 412:173-90
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Longchamp, Alban; Alonso, Florian; Dubuis, Céline et al. (2014) The use of external mesh reinforcement to reduce intimal hyperplasia and preserve the structure of human saphenous veins. Biomaterials 35:2588-99
Vaiyapuri, Sakthivel; Moraes, Leonardo A; Sage, Tanya et al. (2013) Connexin40 regulates platelet function. Nat Commun 4:2564
Fang, Jennifer S; Angelov, Stoyan N; Simon, Alexander M et al. (2013) Compromised regulation of tissue perfusion and arteriogenesis limit, in an AT1R-independent fashion, recovery of ischemic tissue in Cx40(-/-) mice. Am J Physiol Heart Circ Physiol 304:H816-27
Allagnat, F; Klee, P; Cardozo, A K et al. (2013) Connexin36 contributes to INS-1E cells survival through modulation of cytokine-induced oxidative stress, ER stress and AMPK activity. Cell Death Differ 20:1742-52
Munger, Stephanie J; Kanady, John D; Simon, Alexander M (2013) Absence of venous valves in mice lacking Connexin37. Dev Biol 373:338-48
Martin, David; Allagnat, Florent; Gesina, Emilie et al. (2012) Specific silencing of the REST target genes in insulin-secreting cells uncovers their participation in beta cell survival. PLoS One 7:e45844

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