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Vascular permeability, vascular hyperpermeability and angiogenesis.

Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF - Angiogenesis (2008)

Bottom Line: These are the basal vascular permeability (BVP) of normal tissues, the acute vascular hyperpermeability (AVH) that occurs in response to a single, brief exposure to VEGF-A or other vascular permeabilizing agents, and the chronic vascular hyperpermeability (CVH) that characterizes pathological angiogenesis.Finally, we list the numerous (at least 25) gene products that different authors have found to affect vascular permeability in variously engineered mice and classify them with respect to their participation, as far as possible, in BVP, AVH and CVH.Further work will be required to elucidate the signaling pathways by which each of these molecules, and others likely to be discovered, mediate the different types of vascular permeability.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. jnagy@bidmc.harvard.edu

ABSTRACT
The vascular system has the critical function of supplying tissues with nutrients and clearing waste products. To accomplish these goals, the vasculature must be sufficiently permeable to allow the free, bidirectional passage of small molecules and gases and, to a lesser extent, of plasma proteins. Physiologists and many vascular biologists differ as to the definition of vascular permeability and the proper methodology for its measurement. We review these conflicting views, finding that both provide useful but complementary information. Vascular permeability by any measure is dramatically increased in acute and chronic inflammation, cancer, and wound healing. This hyperpermeability is mediated by acute or chronic exposure to vascular permeabilizing agents, particularly vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A). We demonstrate that three distinctly different types of vascular permeability can be distinguished, based on the different types of microvessels involved, the composition of the extravasate, and the anatomic pathways by which molecules of different size cross-vascular endothelium. These are the basal vascular permeability (BVP) of normal tissues, the acute vascular hyperpermeability (AVH) that occurs in response to a single, brief exposure to VEGF-A or other vascular permeabilizing agents, and the chronic vascular hyperpermeability (CVH) that characterizes pathological angiogenesis. Finally, we list the numerous (at least 25) gene products that different authors have found to affect vascular permeability in variously engineered mice and classify them with respect to their participation, as far as possible, in BVP, AVH and CVH. Further work will be required to elucidate the signaling pathways by which each of these molecules, and others likely to be discovered, mediate the different types of vascular permeability.

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(a) Schematic diagram of a normal venule comprised of cuboidal endothelium with prominent VVOs and closed inter-endothelial cell junctions. Note that some VVO vesicles attach to the intercellular cleft below the tight and adherens junction zones. 1 and 2 indicate potential pathways for transcellular (VVO) and intercellular (paracellular) plasma extravasation, respectively. Basal lamina (BL) is intact and the endothelium is completely covered by pericytes. (b) AVH. Acute exposure to VEGF-A causes VVO to open, allowing transcellular passage of plasma contents, possibly by mechanical pulling apart of stomatal diaphragms (3). Others have suggested that fluid extravasation takes place through an opening of intercellular junctions (4, here shown closed). BL and pericyte coverage are as in (a). (c) CVH. Prolonged VEGF-A stimulation causes venular endothelium to transform into MV, greatly thinned, hyperpermeable cells with fewer VVOs and VVO vesicles/vacuoles, degraded BL, and extensive loss of pericyte coverage. Plasma may extravasate either through residual VVO vesicles (5) or through fenestrae (6)
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Fig4: (a) Schematic diagram of a normal venule comprised of cuboidal endothelium with prominent VVOs and closed inter-endothelial cell junctions. Note that some VVO vesicles attach to the intercellular cleft below the tight and adherens junction zones. 1 and 2 indicate potential pathways for transcellular (VVO) and intercellular (paracellular) plasma extravasation, respectively. Basal lamina (BL) is intact and the endothelium is completely covered by pericytes. (b) AVH. Acute exposure to VEGF-A causes VVO to open, allowing transcellular passage of plasma contents, possibly by mechanical pulling apart of stomatal diaphragms (3). Others have suggested that fluid extravasation takes place through an opening of intercellular junctions (4, here shown closed). BL and pericyte coverage are as in (a). (c) CVH. Prolonged VEGF-A stimulation causes venular endothelium to transform into MV, greatly thinned, hyperpermeable cells with fewer VVOs and VVO vesicles/vacuoles, degraded BL, and extensive loss of pericyte coverage. Plasma may extravasate either through residual VVO vesicles (5) or through fenestrae (6)

Mentions: More recently, a structure was discovered in venular endothelium, the vesiculo-vacuolar organelle (VVO), that offers an alternative, trans-endothelial cell route for plasma extravasation in response to permeability factors [44–48]. VVOs are grape-like clusters comprised of hundreds of uncoated, cytoplasmic vesicles and vacuoles that together form an organelle that traverses venular endothelial cytoplasm from lumen to albumen (Figs. 3(a, b), 4a). VVOs often extend to inter-endothelial cell interfaces and their individual vesicles (unlike caveolae) commonly open to the inter-endothelial cell cleft. The vesicles and vacuoles comprising VVOs vary in size from those the size of caveolae to vacuoles with volumes as much as 10-fold larger [49]. These vesicles and vacuoles are linked to each other and to the luminal and abluminal plasma membranes by stomata that are normally closed by thin diaphragms that appear similar to those found in caveolae. We conjectured some years ago that VVOs formed from the linking together of individual caveolae and that larger vesicles and vacuoles resulted from the fusion of two or more caveolae-sized vesicles [49]. Evidence for this was that the smallest VVO vesicles were indistinguishable structurally from caveolae and larger vesicles and vacuoles have volumes that do not fall on a continuum but have a modal distribution, i.e., occur as multiples of the volume of caveolae, the unit vesicle, up to 10-mers. However, VVO vesicles and vacuoles only stain irregularly for caveolin (unpublished data), a protein that is demonstrable by electron microscopic immunocytochemistry in nearly all plasma membrane-connected caveolae. Also, whereas the capillaries in caveolin-1 mice lack caveolae altogether [36], VVOs are present in normal numbers in the venular endothelium of these mice (unpublished data). Whether VVOs somehow take the place of caveolae in caveolin-1 mice and thereby contribute to the increased permeability observed in these animals needs to be investigated.Fig. 3


Vascular permeability, vascular hyperpermeability and angiogenesis.

Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF - Angiogenesis (2008)

(a) Schematic diagram of a normal venule comprised of cuboidal endothelium with prominent VVOs and closed inter-endothelial cell junctions. Note that some VVO vesicles attach to the intercellular cleft below the tight and adherens junction zones. 1 and 2 indicate potential pathways for transcellular (VVO) and intercellular (paracellular) plasma extravasation, respectively. Basal lamina (BL) is intact and the endothelium is completely covered by pericytes. (b) AVH. Acute exposure to VEGF-A causes VVO to open, allowing transcellular passage of plasma contents, possibly by mechanical pulling apart of stomatal diaphragms (3). Others have suggested that fluid extravasation takes place through an opening of intercellular junctions (4, here shown closed). BL and pericyte coverage are as in (a). (c) CVH. Prolonged VEGF-A stimulation causes venular endothelium to transform into MV, greatly thinned, hyperpermeable cells with fewer VVOs and VVO vesicles/vacuoles, degraded BL, and extensive loss of pericyte coverage. Plasma may extravasate either through residual VVO vesicles (5) or through fenestrae (6)
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Related In: Results  -  Collection

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Fig4: (a) Schematic diagram of a normal venule comprised of cuboidal endothelium with prominent VVOs and closed inter-endothelial cell junctions. Note that some VVO vesicles attach to the intercellular cleft below the tight and adherens junction zones. 1 and 2 indicate potential pathways for transcellular (VVO) and intercellular (paracellular) plasma extravasation, respectively. Basal lamina (BL) is intact and the endothelium is completely covered by pericytes. (b) AVH. Acute exposure to VEGF-A causes VVO to open, allowing transcellular passage of plasma contents, possibly by mechanical pulling apart of stomatal diaphragms (3). Others have suggested that fluid extravasation takes place through an opening of intercellular junctions (4, here shown closed). BL and pericyte coverage are as in (a). (c) CVH. Prolonged VEGF-A stimulation causes venular endothelium to transform into MV, greatly thinned, hyperpermeable cells with fewer VVOs and VVO vesicles/vacuoles, degraded BL, and extensive loss of pericyte coverage. Plasma may extravasate either through residual VVO vesicles (5) or through fenestrae (6)
Mentions: More recently, a structure was discovered in venular endothelium, the vesiculo-vacuolar organelle (VVO), that offers an alternative, trans-endothelial cell route for plasma extravasation in response to permeability factors [44–48]. VVOs are grape-like clusters comprised of hundreds of uncoated, cytoplasmic vesicles and vacuoles that together form an organelle that traverses venular endothelial cytoplasm from lumen to albumen (Figs. 3(a, b), 4a). VVOs often extend to inter-endothelial cell interfaces and their individual vesicles (unlike caveolae) commonly open to the inter-endothelial cell cleft. The vesicles and vacuoles comprising VVOs vary in size from those the size of caveolae to vacuoles with volumes as much as 10-fold larger [49]. These vesicles and vacuoles are linked to each other and to the luminal and abluminal plasma membranes by stomata that are normally closed by thin diaphragms that appear similar to those found in caveolae. We conjectured some years ago that VVOs formed from the linking together of individual caveolae and that larger vesicles and vacuoles resulted from the fusion of two or more caveolae-sized vesicles [49]. Evidence for this was that the smallest VVO vesicles were indistinguishable structurally from caveolae and larger vesicles and vacuoles have volumes that do not fall on a continuum but have a modal distribution, i.e., occur as multiples of the volume of caveolae, the unit vesicle, up to 10-mers. However, VVO vesicles and vacuoles only stain irregularly for caveolin (unpublished data), a protein that is demonstrable by electron microscopic immunocytochemistry in nearly all plasma membrane-connected caveolae. Also, whereas the capillaries in caveolin-1 mice lack caveolae altogether [36], VVOs are present in normal numbers in the venular endothelium of these mice (unpublished data). Whether VVOs somehow take the place of caveolae in caveolin-1 mice and thereby contribute to the increased permeability observed in these animals needs to be investigated.Fig. 3

Bottom Line: These are the basal vascular permeability (BVP) of normal tissues, the acute vascular hyperpermeability (AVH) that occurs in response to a single, brief exposure to VEGF-A or other vascular permeabilizing agents, and the chronic vascular hyperpermeability (CVH) that characterizes pathological angiogenesis.Finally, we list the numerous (at least 25) gene products that different authors have found to affect vascular permeability in variously engineered mice and classify them with respect to their participation, as far as possible, in BVP, AVH and CVH.Further work will be required to elucidate the signaling pathways by which each of these molecules, and others likely to be discovered, mediate the different types of vascular permeability.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. jnagy@bidmc.harvard.edu

ABSTRACT
The vascular system has the critical function of supplying tissues with nutrients and clearing waste products. To accomplish these goals, the vasculature must be sufficiently permeable to allow the free, bidirectional passage of small molecules and gases and, to a lesser extent, of plasma proteins. Physiologists and many vascular biologists differ as to the definition of vascular permeability and the proper methodology for its measurement. We review these conflicting views, finding that both provide useful but complementary information. Vascular permeability by any measure is dramatically increased in acute and chronic inflammation, cancer, and wound healing. This hyperpermeability is mediated by acute or chronic exposure to vascular permeabilizing agents, particularly vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A). We demonstrate that three distinctly different types of vascular permeability can be distinguished, based on the different types of microvessels involved, the composition of the extravasate, and the anatomic pathways by which molecules of different size cross-vascular endothelium. These are the basal vascular permeability (BVP) of normal tissues, the acute vascular hyperpermeability (AVH) that occurs in response to a single, brief exposure to VEGF-A or other vascular permeabilizing agents, and the chronic vascular hyperpermeability (CVH) that characterizes pathological angiogenesis. Finally, we list the numerous (at least 25) gene products that different authors have found to affect vascular permeability in variously engineered mice and classify them with respect to their participation, as far as possible, in BVP, AVH and CVH. Further work will be required to elucidate the signaling pathways by which each of these molecules, and others likely to be discovered, mediate the different types of vascular permeability.

Show MeSH
Related in: MedlinePlus