Conclusion

In summary, vascular connexins are central to the structural and functional organization of the vascular bed. Functionally, they are overwhelmingly important for normal vascular development and in the regulation of vascular tone. The formation of gap-junctional channels is a complex process that is subject to plasticity and depends upon cell type and connexin subtype specificity. However, several questions remain. For instance, more needs to be understood with respect to the role of vascular connexins in pathological states. This role may be extensive and highly facilitatory to disease progression, especially in the vascular involvement in inflammation, in atherosclerotic plaque formation, and in abnormalities of blood coagulation. The emerging role of gap junctions in the consideration of vascular patho-biology promises to be fertile ground for future research.

Glossary

Connexin: Channel-forming transmembrane protein subunit. A complete gap junction channel consists of six connexins in one cell pairing with six connexins in an adjacent cell that allow direct transfer of small cyto-plasmic molecules from one cell to an adjacent cell.

Gap junction: Originally defined by electron microscopy as a class of cell-cell contact sites with a uniform ~16-nm "gap" between the cells as opposed to tight junctions that show no gap. Gap junctions consist of an array of connexin-based channels that mediate cell-cell communication.

Heteromeric: A gap junction channel composed of two or more different types of connexins completely intermixed.

Heterotypic: Head-to-head interaction between one type of connexin in one cell and a different type of connexin in an adjacent cell.

Homomeric: A gap junction channel composed of a single type of connexin.

References

1. Das Sarma J., Wang, F., and Koval, M. 2002. Targeted gap junction protein constructs reveal connexin-specific differences in oligomeriza-tion. J. Biol. Chem. 277, 20911-20918.

2. Severs, N. J., Rothery, S., Dupont, E., Coppen, S. R., Yeh, H. I., Ko, Y.S., Matsushita, T., Kaba, R., and Halliday, D. 2001. Immunocyto-chemical analysis of connexin expression in the healthy and diseased cardiovascular system. Microsc. Res. Tech. 52, 301-322.

3. Burt, J. M., Fletcher, A. M., Steele, T. D., Wu, Y., Cottrell, G. T., and Kurjiaka, D. T. 2001. Alteration of Cx43:Cx40 expression ratio in A7r5 cells. Am. J. Physiol. Cell Physiol. 280, C500-C508.

4. Xu, X., Li, W. E., Huang, G. Y., Meyer, R., Chen, T., Luo, Y., Thomas, M. P., Radice, G. L., and Lom C. W. 2001. Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions. J. Cell Biol. 154, 217-230.

5. Kruger, O., Beny, J. L., Chabaud, F., Traub, O., Theis, M., Brix, K., Kirchhoff, S., and Willecke, K. 2002. Altered dye diffusion and upreg-ulation of connexin37 in mouse aortic endothelium deficient in con-nexin40. J. Vasc. Res. 39, 160-172.

6. Simon, A. M., and McWhorter, A. R. 2002. Vascular abnormalities in mice lacking the endothelial gap junction proteins connexin37 and connexin40. Dev. Biol. 251, 206-220.

7. Li, W. E., Waldo, K., Linask, K. L., Chen, T., Wessels, A., Parmacek M. S., Kirby, M. L., and Lo, C. W. 2002. An essential role for con-nexin43 gap junctions in mouse coronary artery development. Development 129, 2031-2042.

8. Sandow, S. L., and Hill, C. E. 2000. Incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat is suggestive of a role in endothelium-derived hyperpolarizing factor-mediated responses. Circ. Res. 86, 341-346.

9. Ying, X., Minamiya, Y., Fu, C., and Bhattacharya, J. 1996. Ca2+ waves in lung capillary endothelium. Circ. Res. 79, 898-908.

10. de Wit, C., Roos, F., Bolz, S. S., Kirchhoff, S., Kruger, O., Willecke, K., and Pohl, U. 2000. Impaired conduction of vasodilation along arterioles in connexin40-deficient mice. Circ. Res. 86, 649-655.

11. Liao, Y., Day, K. H., Damon, D. N., and Duling, B. R. 2001. Endothe-lial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice. Proc. Natl. Acad. Sci. USA. 98, 9989-9994.

12. Navab, M., Liao, F., Hough, G. P., Ross, L. A., Van Lenten, B. J., Rajavashisth, T. B., Lusis, A. J., Laks, H., Drinkwater, D. C., and

Fogelman, A. M. 1991. Interaction of monocytes with cocultures of human aortic wall cells involves interleukins 1 and 6 with marked increases in connexin43 message. J. Clin. Invest. 87, 1763-1772.

13. Zahler, S., Hoffmann, A., Gloe, T., and Pohl, U. 2003. Gap-junctional coupling between neutrophils and endothelial cells: a novel modulator of transendothelial migration. J. Leukoc. Biol. 73, 118-126.

14. Kwak, B. R., Veillard, N., Pelli, G., Mulhaupt, F., James, R. W., Chanson, M., and Mach, F. 2003. Reduced connexin43 expression inhibits atherosclerotic lesion formation in low-density lipoprotein receptor-deficient mice. Circulation 107, 1033-1039.

Further Reading

Brink, P. R. (1998). Gap junctions in vascular smooth muscle. Acta Physiol Scand. 164, 349-356.

Griffith, T. M., Chaytor, A. T., Taylor, H. J., Giddings, B. D., and Edwards, D. H. (2002). cAMP facilitates EDHF-type relaxations in conduit arteries by enhancing electrotonic conduction via gap junctions. Proc. Natl. Acad. Sci. USA 99, 6392-6397. Study using connexin mimetic inhibitory peptides to show that calcium transmission through gap junctions was required for EDHF-type vascular relaxation.

Hill, C. E., Rummery, N., Hickey, H., and Sandow, S. L. (2002). Heterogeneity in the distribution of vascular gap junctions and connexins: Implications for function. Clin. Exp. Pharmacol. Physiol. 29, 620625.

Kruger, O., Plum, A., Kim, J.S., Winterhager, E., Maxeiner, S., Hallas, G., Kirchhoff, S., Traub, O., Lamers, W. H., and Willecke, K. (2000). Defective vascular development in connexin 45-deficient mice. Development 127, 4179-4193. Liao, Y., Day, K. H., Damon, D. N., and Duling, B. R. (2001). Endothelial cell-specific knockout of connexin 43 causes hypotension and bradycardia in mice. Proc. Natl. Acad. Sci. USA 98, 9989-9994. Mice where connexin43 was specifically depleted from endothelial cells using the cre/lox recombinase system were used to demonstrate a role for endothelial connexin43 in regulating blood pressure. Saez, J. C., Berthoud, V. M., Branes, M. C., Martinez, A. D., and Beyer, E. C. (2003). Plasma membrane channels formed by connexins: Their regulation and functions. Physiol Rev. 83, 1359-1400.

Capsule Biography

Dr. Koval's laboratory studies the molecular mechanisms of membrane protein assembly and roles for intercellular communication in regulating pulmonary function. His work on gap junctions started more than a decade ago and is supported by grants from the NIH and American Heart Association.

Dr. Bhattacharya's laboratory investigates intercellular connectivity and coordination in proinflammatory signaling in microvessels. Using lung inflammation as a model, the Bhattacharya group has developed optical imaging methods to quantify signaling mechanisms in cells in situ.

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Essentials of Human Physiology

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