The long-term goal of this project is to understand the role that gap junction-mediated communication plays in regulating vascular responses and to define the contributions of specific gap junction proteins. Gap junctions are clusters of intercellular channels, comprised of connexin (Cx) proteins, that connect the cytoplasm of adjacent cells, allowing the direct cell-to-cell transfer of small molecules. Alterations in Cx expression and function have been correlated with hypertension, ischemia, inflammation, atherosclerosis, atrial fibrillation, and heart failure. In addition, Cx mutations or altered Cx expression caused by other gene mutations could be responsible for congenital defects of the heart and vasculature. This project takes advantage of the availability of knockout mice lacking specific vascular Cxs to study Cx function in the vasculature. In the first specific aim, the role of Cx37 and Cx40 in vascular development and angiogenesis is investigated. A variety of methods are used to explore the mechanism of abnormal vessel formation in mice lacking both Cx37 and Cx40, including use of an endothelial cell-specific reporter gene, cell proliferation assays, and apoptosis assays. Primary endothelial cell cultures are prepared to directly compare proliferation and apoptosis in the presence or absence of specific Cxs. The effect of exogenous expression of Cxs on cell growth and apoptosis is also examined in cell cultures. Angiogenic responses in Cx-deficient and wild-type mice are compared using both an in vivo assay and an explant approach.
A second aim i s to determine if Cx37 and Cx40 form channels of mixed composition and unique functional properties in vascular endothelial cells, using electrophysiological and biochemical methods. Heteromeric channels could play an important role in determining the types of signals that are communicated during vascular development, angiogenic responses, and vasomotor responses. Understanding the phenotypes of Cx deficient mice may provide insight into congenital vascular defects in humans and could also shed light on the processes that regulate normal vascular development. A better understanding of vascular Cxs could lead to new insights, treatments, and prevention for congenital vascular defects and cardiovascular disease. Finally, these studies could also lead to new approaches to control vasculogenesis and angiogenesis in other clinically important settings, such as anti-angiogenesis treatments designed to fight cancer.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064232-08
Application #
7618654
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Goldman, Stephen
Project Start
1999-12-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
8
Fiscal Year
2009
Total Cost
$256,587
Indirect Cost
Name
University of Arizona
Department
Physiology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Munger, Stephanie J; Davis, Michael J; Simon, Alexander M (2017) Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43. Dev Biol 421:204-218
Alonso, Florian; Domingos-Pereira, Sonia; Le Gal, Loïc et al. (2016) Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion. Oncotarget 7:14015-28
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
Kanady, John D; Munger, Stephanie J; Witte, Marlys H et al. (2015) Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling. Dev Biol 405:33-46
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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