Macrovascular Endothelium

□ Derived from angiogenesis

□ More sensitive to barrier disruption by endotoxin

□ More sensitive to barrier disruption by store-operated Ca2+ entry

□ More sensitive to VEGF-induced chemotaxis

□ More sensitive to TNFa-induced cell detachment

Microvascular Endothelium

□ Derived from vasculogenesis

□ Fourfold higher cell surface area G Fewer visible gaps on EM

D Tenfold higher basal monolayer resistance

□ Higher cAMP levels

□ Higher expression of VE-cadherin

□ More sensitive to barrier disruption by VE-cadherin antibodies

□ More sensitive to barrier disruption by thrombin

Figure 2 Differential barrier properties of endothelial phenotypes. The diagram shows the cross section of a blood vessel extending from the proximal large arteries to the small microvessels. Listed beneath each broad category of endothelium are specific characteristics related to differences in barrier function between these vascular areas.

to macrovascular ECs relative to microvessel ECs. The contribution of these mechanical forces to differential EC permeability is still incompletely understood.

Glossary

Cytoskeleton: Framework of structural proteins necessary for cell shape and movement. The three primary components are actin microfilaments, microtubules, and intermediate filaments.

Myosin light chain kinase (MLCK): A Ca2+/calmodulin, ATP-dependent enzyme that phosphorylates myosin light chains on serine-19 and threonine-18, which results in increased actomyosin interaction. MLCK activity is a necessary step in many models of vascular permeability.

Sphingosine 1-phosphate (S1P): A biologically active phospholipid generated by hydrolysis of membrane lipids, S1P is produced in significant quantities by circulating platelets and has potent EC barrier-enhancing and chemotactic properties.

Thrombin: A central regulatory molecule in the coagulation cascade, thrombin produces potent EC barrier disruption through stimulation of actomyosin interaction, stress fiber formation, contraction, and intercellular gap formation.

Bibliography/Further Reading

Aird, W. C. (2003). Endothelial cell heterogeneity. Crit. Care Med. 31, S221-S230. This article describes structural and functional differences in EC subpopulations and applies this knowledge to an understanding of vasculopathic processes, especially acute lung injury.

Amano, M., Chihara, K., Kimura, K., Fukata, Y., Nakamura, N., Matsuura, Y., and Kaibuchi, K. (1997). Formation of actin stress fibers and focal adhesions enhanced by rho-kinase. Science 275, 1308-1311.

Corada, M., Mariotti, M., Thurston, G., Smith, K., Kunkel, R., Brockhaus, M., Lampugnani, M. G., Martin-Padura, I., Stoppacciaro, A., Ruco, L., McDonald, D. M., Ward, P. A., and Dejana, E. (1999). Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo. Proc. Natl. Acad. Sci. USA 96, 9815-9820.

Dudek, S. M., and Garcia, J. G. N. (2001). Cytoskeletal regulation of pulmonary vascular permeability. J. Appl. Physiol. 91, 1487-1500. A recent review by this chapter's first author, this article explores EC cytoskeletal components and mechanisms of barrier regulation in greater detail than is possible here.

Garcia, J. G., Siflinger-Birnboim, A., Bizios, R., Del Vecchio, P. J., Fenton, J. W., and Malik, A. B. (1986). Thrombin-induced increase in albumin permeability across the endothelium. J. Cell Physiol. 128, 96-104.

Garcia, J. G. N., Liu, F., Verin, A. D., Birukova, A., Dechert, M. A., Gerthoffer, W. T., Bamburg, J. R., and English, D. (2001) Sphingosine

1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J. Clin. Invest. 108, 689-701. This novel work represents the initial report describing the potent barrier-enhancing effects of S1P and the cytoskeletal changes involved in producing this response.

Goeckeler, Z. M., and Wysolmerski, R. B. (1995). Myosin light chain kinase-regulated endothelial cell contraction: The relationship between isometric tension, actin polymerization, and myosin phosphorylation. J. Cell Biol. 130, 613-627.

Kelly, J. J., Moore, T. M., Babal, P., Diwan, A. H., Stevens, T., and Thompson, W. J. (1998). Pulmonary microvascular and macrovascular endothelial cells: Differential regulation of Ca2+ and permeability. Am. J. Physiol. 274, L810-L819.

Michel, C. C., and Curry, F. E. (1999). Microvascular permeability. Physiol. Rev. 79, 703-761. This extensive review discusses classical structural questions about microvascular permeability using recent experimental work on intact microvascular beds, single perfused microvessels, and EC cultures. Wojciak-Stothard, B., and Ridley, A. J. (2002). Rho GTPases and the regulation of endothelial permeability. Vascul. Pharmacol. 39, 187-199.

This article summarizes the antagonistic effects of Rho and Rac small GTPases on EC barrier function.

Capsule Biography

Dr. Dudek is a faculty member of the Division of Pulmonary and Critical Care Medicine of the Johns Hopkins School of Medicine. His research focuses on the cytoskeletal regulation of pulmonary vascular permeability in acute lung injury syndromes and is supported by grants from the NIH.

Dr. Finigan is a research fellow performing similar studies in the Division of Pulmonary and Critical Care Medicine of the Johns Hopkins School of Medicine.

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