Vascular permeability, vascular hyperpermeability and angiogenesis - PubMed (original) (raw)

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Vascular permeability, vascular hyperpermeability and angiogenesis

Janice A Nagy et al. Angiogenesis. 2008.

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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Figures

Fig. 1

Fig. 1

Miles permeability assay. Various test substances were injected intradermally into the shaved and depilated flank skin of a Hartley guinea pig, followed immediately by an intravenous injection of Evan’s blue dye. Animal was photographed 30 min later. Injected materials were as follows: 1, Neutralizing antibody against VEGF-A; 2 and 5, ascites tumor-associated VEGF-A; 3 and 6, ascites tumor associated VEGF-A plus control immunoglobulin; 4 and 7, ascites tumor-associated VEGF-A plus specific VEGF-A neutralizing antibody. Reproduced from [93]

Fig. 2

Fig. 2

Upper panel: Electron micrograph illustrating a typical capillary endothelial cell with numerous caveolae. Many of these are connected to the luminal or abluminal plasma membranes (arrows), whereas others are in the cytoplasm. L, lumen scale bar, 100 nm. Lower panel: Schematic diagram illustrating pathways by which molecules can cross the capillary barrier. (1) intercellular cleft; (2) caveolae that may shuttle across the capillary or form a chain of vesicles that connect the lumen and albumen. BL, basal lamina

Fig. 3

Fig. 3

Transmission electron micrographs of venules in normal mouse ear skin (a, b) and of a mother vessel (c, d) 3 days after local injection of Ad-VEGF-A164. (a, b) Typical normal venules lined by cuboidal endothelium. The cytoplasm contains prominent vesiculo-vacuolar organelles (VVOs) and is enveloped by a complete coating of pericytes (P). R, red blood cell. (c, d) MV are greatly enlarged vessels that are characterized by extensive endothelial cell thinning; striking reduction in VVOs and other cytoplasmic vesicles; prominent nuclei that project into the vascular lumen; frequent mitotic figures (arrows, c); endothelial cell bridging with the formation of multiple lumens (L, d); and pericyte (P) detachment in (c). The mother vessel lumen (c) is packed with red blood cells, indicative of extensive plasma extravasation. Inset. The normal venule depicted in a is reproduced in c at the same magnification as the mother vessel to illustrate differences in relative size of normal venules and MV. Scale bars: (a, b) 1 μm; (c, d) 5 μm

Fig. 4

Fig. 4

(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)

Fig. 5

Fig. 5

Electron micrographs of portions of a MV (a) and a GMP (b) at 5 and 10 days following local injection of Ad-VEGF-A164 into nude mouse ears and 30 min after i.v. injection of ferritin tracer. (a) MV endothelium is greatly thinned and spanned by no more than 1–3 vesicles/vacuoles. Ferritin (dark-black particles) fill vascular lumens (L), are present in VVO vesicles/vacuoles, and have extravasated into the extravascular space (some encircled). (b) GMP with extensively thinned and fenestrated endothelium. Ferritin is present in lumen, occasional residual cytoplasmic vesicles (white arrows) and in extravascular space, some encircled. p, pericyte. Scale bars, 200 nm. Reprinted in revised form from [20]

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