Optimality in the developing vascular system: Branching remodeling by means of intussusception as an efficient adaptation mechanism

Abstract

The theory of bifurcating vascular systems predicts vessel diameters that are related to optimality criteria like minimization of pumping energy or of building material. However, mechanisms for producing the postulated optimality have not been described so far, and quantitative data on bifurcation diameters during development are scarce. We used an embryonic vascular bed that rapidly grows and adapts to changing hemodynamic conditions, the chicken chorioallantoic membrane (CAM), and correlated vascular cast and tissue section morphology with in vivo time-lapse video monitoring. The bifurcation exponent ⌬ and associated parameters were quantitatively assessed in arterial and venous microvessels ranging in diameter from 30 to 100 m. We observed emergence of optimality by means of intussusception, i.e., formation of transvascular tissue pillars. In addition to intussusceptive microvascular growth (IMG ‫؍‬ expansion of capillary networks) and intussusceptive arborization (IAR ‫؍‬ formation of feeding vessels from capillaries) the observed intussusception at bifurcations represents a third variant of nonsprouting angiogenesis. We call it intussusceptive branching remodeling (IBR). IBR occurred in vessels of considerable diameter by means of two alternative mechanisms: either through pillars arising close to a bifurcation, which increased in girth until they merged with the connective tissue in the bifurcation angle; or through pillars arising at some distance from the bifurcation point, which then expanded by formation of ingrowing tissue folds until they became connected to the tissue of the bifurcation angle. Morphologic evidence suggests that IBR is a wide-spread phenomenon, taking place also in lung, intestinal, kidney, eye, etc., vasculature. Irrespective of the mode followed, IBR led to a branching pattern close to the predicted optimum, ⌬ ‫؍‬ 3.0. Significant differences were observed between ⌬ at arterial bifurcations (2.70 to 2.90) and ⌬ at venous bifurcations (2.93 to 3.75). IBR, by means of eccentric pillar formation and fusion, was also involved in vascular pruning. Experimental changes in CAM hemodynamics (by locally increasing blood flow) induced onset of IBR within less than 1 hr. Our study provides morphologic and quantitative evidence that a similar cellular machinery is used for all three variants of vascular intussusception, IMG, IAR, and IBR. It thus provides a mechanism of efficiently generating complex blood transport systems from limited genetic information. Differential quantitative outcome of IBR in arteries and veins, and the experimental induction of IBR strongly suggest that hemodynamic factors can instruct embryonic vascular remodeling toward optimality.

Inhibition of Notch signaling induces extensive intussusceptive neo-angiogenesis by recruitment of mononuclear cells

“…Vascular casts were prepared as previously described [35]. Briefly, CAM vasculature/the vasculature of the murine liver were perfused with a freshly prepared solution of Mercox Ò (Vilene Company, Japan) containing 0.1 mL of accelerator per 5 mL of resin.…”

Intussusceptive angiogenesis: Its emergence, its characteristics, and its significance

“…6a,b; Djonov et al, 2002). The area containing the pillar documented in Figure 6b was fixed, embedded, and processed for electron microscopic investigation.…”

Vascular localization and proliferation in the growing tip of the deer antler

“…Other possibilities include the process of sprouting of new vessels or of intussusceptive remodeling, whereby the lower branches fuse with, or are removed from, the main artery (Carmeliet and Jain, 2000b). Intussusceptive remodeling has been described by others but is often associated with the formation or proximal movement of arterial branches (Carmeliet and Jain, 2000b;Burri and Djonov, 2002;Djonov et al, 2002;Burri et al, 2004).…”