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Historical Perspective: Centenary Series: 4 |
1 Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, CA, USA
(Received 7 December 2007;
accepted after revision 4 January 2008; first published online 15 March 2008)
Corresponding author F.-R. E. Curry: Department of Physiology and Membrane Biology, School of Medicine, One Shields Avenue, University of California, Davis, CA 95616, USA. Email: fecurry{at}ucdavis.edu
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) of the microvessel wall to albumin and other test solutes. This parameter describes the selectivity of the capillary wall to solutes and provides a second independent estimate of changes in microvessel permeability. Paired measurements of Lp and have proved an invaluable tool in the investigation of inflammation and oedema formation. The primary limitation of these microperfusion methods is that microvessels smaller that 10 µm (most mammalian true capillaries) are difficult to cannulate and perfuse using red cells as flow markers.
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The modified Landis microperfusion approach also enabled direct comparison of microvessel permeability coefficients before and after each microvessel was exposed to conditions that modified the permeability of the microvessel wall. This approach has been used not only in frog mesentery but also in frog skeletal muscle, rat and mouse mesentery and kidney and is the basis for on-going investigations. These include the action of vascular endothelial growth factor isoforms in the regulation of microvessel permeability (see Glass et al. 2006), the modulation of microvessel permeability by activated, but not just adherent leukocytes (Zhu & He, 2006), and the complex interactions of nitric oxide with microvascular cells (Rumbaut et al. 2000). In addition, a combination of microperfusion and electron microscopy on sections of the perfused microvessel has allowed the ultrastructure of the vessel wall to be investigated in microvessels of precisely known permeability. This approach was used to demonstrate that the endothelial glycocalyx was the principal molecular filter at the capillary wall and led to the development of the ‘fibre matrix’ theory of capillary permeability. This provided a major new perspective on the classical ‘small pore’ theory of capillary permeability (see Michel & Curry, 1999, and a review by Weinbaum et al. 2007, of recent papers on the role of the glycocalyx in microvascular function).
It is interesting to note that the paper was published at the beginning of the era of culturing endothelial cells and measuring the permeability properties of endothelial monolayers as models of permeability barriers in continuous endothelium. Cultured endothelial monolayers are much more permeable than those in intact microvessels, even the relatively high values in frog mesenteric microvessels reported by Michel et al. (1974). Microperfusion in combination with in vivo fluorescent imaging methods and immunocytochemistry have enabled evaluation the contribution of cellular and molecular mechanisms to the regulation of permeability in intact microvessels. Examples include paired measurements of Lp and cytoplasmic calcium ion concentration to evaluate calcium-dependent signalling pathways in intact microvessels, and recent evaluations of cAMP-dependent mechanisms regulating endothelial cell-to-cell adhesion. Using a combination of microperfusion and sterile technique, workers from our laboratory have demonstrated that venular microvessels in rat mesentery respond to thrombin (a common mediator of increased permeability in cultured endothelial monolayers) only when recannulated and perfused 24 h after prior exposure to inflammatory conditions. Thus, endothelial phenotypes expressed under some culture conditions may be more characteristic of those in the walls of microvessels that have been exposed to inflammatory conditions than the normal permeability state in perfused microvessels (Curry et al. 2003).
It is safe to conclude that the methods used to measure permeability in perfused microvessels from this classic paper by Michel et al. (1974) will continue to be a very direct way to investigate the regulation of fluid and solute exchange in the microcirculation and to provide a crucial check on the pertinence of information obtained from cultured endothelial monolayers to microvascular function.
References
Curry FE, Zeng M & Adamson RH (2003). Thrombin increases permeability only in venules exposed to inflammatory conditions. Am J Physiol Heart Circ Physiol 285, H2446–2453.
Glass CA, Harper SJ & Bates DO (2006). The anti-angiogenic VEGF isoform VEGF165b transiently increases hydraulic conductivity, probably through VEGF receptor 1 in vivo. J Physiol 572, 243–57.
Michel CC & Curry FE (1999). Microvascular permeability. Physiol Rev 79, 703–761.
Michel CC, Mason JC, Curry FE, Tooke JE & Hunter (1974). A development of theLandis technique for measuring the filtration coefficient of individual capillaries in the frog mesentery. Q J Exp Physiol 59, 287–309.
Rumbaut RE, Wang J & Huxley VH (2000). Differential effects of L–NAME on rat venular hydraulic conductivity. Am J Physiol Heart Circ Physiol 279, H2017–2023.
Weinbaum S, Tarbell JM & Damiano ER (2007). The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 9, 121–167.[CrossRef][Medline]
Zhang X, Adamson RH, Curry FE & Weinbaum S (2008). Transient regulation of transport by pericytes in post capillary venules. Proc Natl Acad Sci 105, 1374–1379.
Zhu L & He P (2006). fMLP-stimulated release of reactive oxygen species from adherent leukocytes increases microvessel permeability. Am J Physiol Heart Circ Physiol 290, H365–372.
Acknowledgements
The author's research is supported by NIH grants HL28607 and HL44485. The photograph of Charles Michel is by M. E. Rosenberg.
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