Conclusions

The discovery of NO has led to the identification of multiple physiological roles for this gaseous second messenger in the microcirculation. We surmise that the local autocrine actions of NO that govern inflammation and vascular permeability in the microcirculation may be as important as its vasodilatory role in conduit vessels. Furthermore, the diverse function of NO may extend beyond the vascular bed. Recent findings using NOS inhibitors and eNOS (-/-) mice revealed an important role of endothelial derived nitric oxide in mediating lymphatic fluid flow in the microlym-phatic network (new reference #12). Therefore, future mechanistic studies and the development of novel reagents to faithfully manipulate the NO-sGC-PKG pathway will help dissect the physiological importance of NO in the microcirculation and microlymphatic beds.

Glossary

Endothelium: The innermost layer of cells lining all blood vessels. Nitric oxide: A free radical gas produced by the enzyme nitric oxide synthase.

Permeability: The leakage of fluid or proteins from the circulation after tissue injury.

Vasodilation: Dilation of a blood vessel to increase blood flow.

References

1. Meng, W., Ma, J., Ayata, C., Hara, H., Huang, P. L., Fishman, M. C., and Moskowitz, M. A. (1996). ACh dilates pial arterioles in endothelial and neuronal NOS knockout mice by NO-dependent mechanisms. Am. J. Physiol. 271, H1145-1150.

2. Sun, D., Huang, A., Smith, C. J., Stackpole, C. J., Connetta, J. A., Shesely, E. G., Koller, A., and Kaley, G. (1999). Enhanced release of prostaglandins contributes to flow-induced arteriolar dilation in eNOS knockout mice. Circ. Res. 85, 288-293.

3. Payne, G. W., Madri, J. A., Sessa, W. C., and Segal, S. S. (2003). Abolition of arteriolar dilation but not constriction to histamine in cremaster muscle of eNOS-/-mice. Am. J. Physiol. Heart Circ. Physiol. 285, H493-498.

4. McMahon, T. J., Moon, R. E., Luschinger, B. P., Carraway, M. S., Stone, A. E., Stolp, B. W., Gow, A. J., Pawloski, J. R., Watke, P., Singel, D. J., Piantadosi, C. A., and Stamler, J. S. (2002). Nitric oxide in the human respiratory cycle. Nat. Med. 8, 711-717.

5. Nase, G. P., Tuttle, J., and Bohlen, H. G. (2003). Reduced perivascular PO2 increases nitric oxide release from endothelial cells. Am. J. Phys-iol. Heart Circ. Physiol. 285, H507-515.

6. Freedman, J. E., Sauter, R., Battinelli, E. M., Ault, K., Knowles, C., Huang, P. L., and Loscalzo, J. (1999). Deficient platelet-derived nitric oxide and enhanced hemostasis in mice lacking the NOSIII gene. Circ. Res. 84, 1416-1421.

7. Cerwinka, W. H., Cooper, D., Krieglstein, C. F., Feelisch, M., and Granger, D. N. (2002). Nitric oxide modulates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules. Am. J. Physiol. Heart Circ. Physiol. 282, H1111-1117.

8. Lefer, D. J., Jones, S. P., Girod, W. G., Baines, A., Grisham, M. B., Cockrell, A. S., Huang, P. L., and Scalia, R. (1999). Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice. Am. J. Physiol. 276, H1943-1950.

9. Fukumura, D., Gohongi, T., Kadambi, A., Izumi, Y., Ang, J., Yun, C. O., Buerk, D. G., Huang, P. L., and Jain, R. K. (2001). Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc. Natl. Acad. Sci. USA 98, 2604-2609.

10. Bucci, M., Gratton, J. P., Rudic, R. D., Acevedo, L., Roviezzo, F., Cirino, G., and Sessa, W. C. (2000). In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation. Nat. Med. 6, 1362-1367.

11. Zhu, L., Schwegler-Berry, D., Castranova, V., and He, P. (2004). Internalization of caveolin-1 scaffolding domain facilitated by Antennapedia homeodomain attenuates PAF-induced increase in microvessel permeability. Am. J. Physiol. Heart Circ. Physiol. 286, H195-201.

12. Hagendoorn, J., Padera, T. P., Kashiwagi, S., Isaka, N., Noda, F., Lin, M. I., Huang, P. L., Sessa, W. C., Fukumura, D., and Jain, R. K. (2004). Endothelial nitric oxide synthase regulates microlymphatic flow via collecting lymphatics. Circ. Res. 95, 204-209.

Bibliography

Dvorak, H. F. (2002). Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J. Clin. Oncol. 20, 4368-4380.

Cirino, G., Fiorucci, S., and Sessa, W. C. (2003). Endothelial nitric oxide synthase: The Cinderella of inflammation? Trends Pharmacol. Sci. 24, 91-95. Review examining the concept that the endothelial isoform of nitric oxide synthase can promote inflammation.

Hobbs, A. J., Higgs, A., and Moncada, S. (1999). Inhibition of nitric oxide synthase as a potential therapeutic target. Ann. Rev. Pharmacol. Toxicol. 39, 191-220.

Liu, L., and Kubes, P. (2003). Molecular mechanisms of leukocyte recruitment: Organ-specific mechanisms of action. Thromb. Haemos. 89, 213-220.

Michel, C. C., and Curry, F. R. (1999). Microvascular permeability. Phys-iol. Rev. 79, 703-761. Thorough review describing the experimental evidence for the mechanisms of vascular permeability.

Papapetropoulos, A., Rudic, R. D., and Sessa, W. C. (1999). Molecular control of nitric oxide synthases in the cardiovascular system. Cardiovasc. Res. 43, 509-520. Analysis of the roles of nitric oxide synthases in the cardiovascular system based on phenotypes observed in genetically deficient mice.

Walford, G., and Loscalzo, J. (2003). Nitric oxide in vascular biology.

Capsule Bibliography

Dr. Sessa is a Professor in the Department of Pharmacology at Yale University and the Director of the Vascular Cell Signaling and Therapeutics Program. His laboratory research focuses on identifying cell biological and molecular pathway that influence the function of blood vessels during vessel remodeling, angiogenesis, and inflammation. His work is funded from the NIH.

Ms. Michelle I. Lin is a Ph.D. student examining how nitric oxide regulates vascular permeability.

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