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Trans-NIH Angiogenesis Workshop; May 20-21, 2013
  • Abstracts

    Multiplicative Expansion of Microvascular Network: Intussusceptive Angiogenesis

    Steven J. Mentzer, MD  [ View bio ]
    (Harvard Medical School, Boston, MA)

    Intussusceptive angiogenesis, largely unseen by light microscopy, is a dynamic process capable of dramatically modifying the structure of the microcirculation. The initial structural feature of intussusceptive angiogenesis is the intussusceptive pillar; a cylindrical microstructure less than 5um in diameter that spans the lumen of a blood vessel. Pillars have been identified in tissues as diverse as the Chick chorioallantoic membrane (CAM) and the regenerating rodent lung and human cancer. Pillars are typically identified by the analysis of vascular corrosion casts with scanning electron microscopy (SEM). Ultrastructural studies using transmission electron microscopy (TEM) suggest that pillars develop from the transluminal protrusion of endothelial cell membranes. Although the early phases of pillar formation identified by TEM and SEM typically reflect cylindrical microstructures, later imaging indicates that intussusceptive pillars can grow and extend to create duplicated and remodeled blood vessels. Pillar extension down the axis of the vessel can efficiently duplicate the vessel without the need for endothelial cell proliferation. Similarly, pillar extension in non-axial directions can prune vessel branches or remodel vessel angles. The influence of blood flow on pillar extension has been studied using intravital microscopy and 3-D finite element models of intussusceptive angiogenesis in both murine colitis and the chick CAM. Based on measurable flow dynamics and essential structural features of the blood vessels identified by intravital microscopy, these computational models have mapped the distribution of mechanical forces within the vessels containing intussusceptive pillars. In addition, the finite element flow models have facilitated computational "pillar deletion" experiments; that is, the calculation of force distribution in the same vessel with and without intraluminal pillars. These studies suggest that individual pillars, or the first pillar in a series of pillars, form in regions of the vessel with minimal shear stress. In low or variable flow conditions, pillars are primarily located in microhemodynamic "dead zones" within the vessel and are constrained by high shear stress. In high flow conditions, intussusceptive angiogenesis can be triggered by an intraluminal stimulus such as in enhanced blood flow. In skeletal muscle, chronic treatment with the alpha-adrenergic antagonist prazosin results in a 3-fold increase in blood flow that triggers both pillar formation and capillary replication. In both low and high flow conditions, the location of the pillar within the flow stream provides an opportunity for local exposure to a variety of blood-borne elements including soluble factors and progenitor cells. The possibility of blood-borne progenitor cells contributing to pillar extension has been studied using a wild-type/GFP parabiotic cross-circulation model of lung regeneration and acute colitis. These studies have shown that blood-borne GFP+/CD34+ cells localize to regions of the microcirculation associated with intussusceptive pillars. Importantly, these results suggest a mechanism of pillar expansion that does not depend upon endothelial cell proliferation or capillary sprouting. Intussusceptive angiogenesis appears to provide a potential mechanism for both the localization of blood-borne progenitor cells and the rapid therapeutic expansion of microvascular networks.

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Workshop Organizer: NIH

NCI:Nancy Emenaker, PhD, RD
Suzanne Forry-Schaudies, PhD
NHLBI:Yunling Gao, MD, PhD
NIDDK: Teresa Jones, MD

NIH - National Institutes of Health: Turning Discovery Into Health

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