The Basic Concept of Intussusception

Nonsprouting angiogenesis by intussusception was first described in the capillary bed of neonatal rat lungs by Caduff and coworkers [1]. Analyzing scanning electron micrographs of lung vascular corrosion casts, the authors detected a multitude of tiny holes with diameters up to 2 mm. Serial sectioning of lung tissue followed by transmission electron microscopy revealed these structures to correspond to transluminal tissue pillars [1, 2]. Four consecutive steps for pillar formation have been postulated:

• Phase I: Simultaneous protrusions of opposite capillary walls into the vessel lumen lead to the creation of an interendothelial contact zone across the capillary lumen.

• Phase II: Reorganization of the interendothelial cell junctions followed by central perforation of the sandwich-like structure composed of two basal membranes and two endothelial leaflets.

• Phase III: Formation of the interstitial pillar core by invasion of cell processes of pericytes and myofibroblasts; appearance of collagen fibrils. During these first three phases, the transluminal pillars are still very slender, mostly with diameters less than 2.5 mm.

• Phase IV: The pillars increase in girth by further deposition of material and cells, but without changes in their basic structure.

The concept of intussusception is schematically represented in Figure 1.

In the meantime, it could be demonstrated that transcap-illary tissue pillars could be produced by several alternative mechanisms to the one described above. For details, the reader is referred to a recent review [3].

To describe the new angiogenic process, the authors coined the term intussusception to convey the meaning that creation of new capillary segments occurs by insertion of transcapillary pillars (i.e., by growth "within itself"). They postulated that the microvasculature of the developing lung was predominantly growing by intussusception, a phenomenon that had not been described hitherto and termed it intussusceptive microvascular growth (IMG) [1, 2].

The complex spatial structure of transluminal pillars, their small size, and the need of three-dimensional analysis

Figure 1 Three-dimensional (a-d) and two-dimensional (a'-d') drawings illustrating intussusceptive pillar formation. The process begins with the protrusion of opposite capillary walls into the vessel lumen (a, b, a', b'). After establishing an interendothelial contact (c, c'), the endothelial bilayer and the basement membranes (BM) are perforated centrally. The newly formed pillar increases in girth after being invaded by pericytes (Pr) and fibroblasts (Fb), which produce collagen fibrils (Co) (d, d'). Corresponding three-dimensional visualization of transluminal pillars in capillary plexus of chicken CAM. In corrosion casts of blood vessels, newly formed transcapillary pillars appear as small holes (asterisks) (e); three-dimensional reconstruction of a pillar based on transmission electron microscopic analysis of serial sections (f). An erythrocyte (Er) is seen behind the pillar. Bars: e and f = 5 mm. (a-d'). Reproduced from Kurz et al. 2003 [8] and (e, f) from Djonov et al. 2000 [4] with the authors' and publisher's permission. (see color insert)

Figure 1 Three-dimensional (a-d) and two-dimensional (a'-d') drawings illustrating intussusceptive pillar formation. The process begins with the protrusion of opposite capillary walls into the vessel lumen (a, b, a', b'). After establishing an interendothelial contact (c, c'), the endothelial bilayer and the basement membranes (BM) are perforated centrally. The newly formed pillar increases in girth after being invaded by pericytes (Pr) and fibroblasts (Fb), which produce collagen fibrils (Co) (d, d'). Corresponding three-dimensional visualization of transluminal pillars in capillary plexus of chicken CAM. In corrosion casts of blood vessels, newly formed transcapillary pillars appear as small holes (asterisks) (e); three-dimensional reconstruction of a pillar based on transmission electron microscopic analysis of serial sections (f). An erythrocyte (Er) is seen behind the pillar. Bars: e and f = 5 mm. (a-d'). Reproduced from Kurz et al. 2003 [8] and (e, f) from Djonov et al. 2000 [4] with the authors' and publisher's permission. (see color insert)

Intussusception Can Occur Only in a Perfused Vascular Bed

All commonly used in vitro and in vivo experimental tools, such as three-dimensional collagen gels, corneal implants, tumor implantation, wound healing, and embryonic grafting, will originally induce capillary sprouting during early tissue neovascularization. Intussusception would not be expected to occur initially in these models because (1) the facts that the tissue has first to be "colonized" by endothelial cells and (2) the absence of blood flow. Our own investigations indicated that hemodynamic factors are essential players in regulatory mechanisms of intussusception [7]. This could be an additional reason why intussusception has not been recognized until recently.

Blood Vessel Segments Are Generated More Rapidly by Intussusception than by Sprouting

As mentioned previously, sprouting is a relatively sluggish process, requiring a few days for initiation, implementation, and finally integration of the newly formed segments into the vascular system. Using improved in vivo monitoring combined with histological and ultrastructural analyses of serial tissue sections, pillar formation has been demonstrated to require a period of four to five hours for completion. Under conditions of artificially accelerated blood flow, this period was reduced to one hour only [4, 5, 7]. This swiftness could explain how the capillary network of the eye choroid or of the chorio-allantoic membrane (CAM) of the chicken could increase 25 and 100 times, respectively, in disk surface just within a few days. The augmentation of the vascular exchange surface area and vascular volume was much higher even. Similarly, in the lung vasculature during the early postnatal period, the capillary volume and surface area increase thirty-fivefold and twentyfold, respectively [4, 5, 7-9].

for their visualization may explain why intussusception was overlooked in the past. The only reliable methods to recognize transluminal pillars safely are vascular corrosion casting visualized by scanning electron microscopy, serial sectioning for light or transmission electron microscopy followed by three-dimensional reconstruction (Figure 1) or, alternatively, confocal laser microscopy [4-7]. Other methods, such as nuclear magnetic resonance, microcomputer tomography, angiography, and ultrasonics even adapted for small objects do not have the resolution (below 1 mm) needed for visualizing pillars.

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