Intussusceptive angiogenesis: expansion and remodeling of microvascular networks

Abstract

Intussusceptive angiogenesis is a dynamic intravascular process capable of dramatically modifying the structure of the microcirculation. The distinctive structural feature of intussusceptive angiogenesis is the intussusceptive pillar—a cylindrical microstructure that spans the lumen of small vessels and capillaries. The extension of the intussusceptive pillar appears to be a mechanism for pruning redundant or inefficient vessels, modifying the branch angle of bifurcating vessels and duplicating existing vessels. Despite the biological importance and therapeutic potential, intussusceptive angiogenesis remains a mystery, in part, because it is an intravascular process that is unseen by conventional light microscopy. Here, we review several fundamental questions in the context of our current understanding of both intussusceptive and sprouting angiogenesis. 1) What are the physiologic signals that trigger pillar formation? 2) What endothelial and blood flow conditions specify pillar location? 3) How do pillars respond to the mechanical influence of blood flow? 4) What biological influences contribute to pillar extension? The answers to these questions are likely to provide important insights into the structure and function of microvascular networks.

Brain angioarchitecture and intussusceptive microvascular growth in a murine model of Krabbe disease

“…A distinguishing anatomic feature of intussusceptive angiogenesis is the intussusceptive pillar, a transluminal tissue bridge that spans the vessel lumen. Physical expansion or growth of the pillar along the vessel axis divides the lumen resulting in vascular duplication [23]. Even though the molecular mechanisms leading to intussusceptive angiogenesis are not fully elucidated, recent observations have shown that inhibition of Notch signaling in already existing vascular beds induces extensive intussusceptive angiogenesis [24].…”

“…Intussusceptive angiogenesis is distinct from sprouting angiogenesis because it does not require cell proliferation. It might represent a general fast recovery adaption of vascularization to growth necessities with a rapid expansion of the existing microvascular network [23]. In inflammatory tissue, a shift is observed from sprouting angiogenesis toward intussusceptive angiogenesis [23].…”

“…It might represent a general fast recovery adaption of vascularization to growth necessities with a rapid expansion of the existing microvascular network [23]. In inflammatory tissue, a shift is observed from sprouting angiogenesis toward intussusceptive angiogenesis [23]. Thus, the dynamic process of intussusceptive angiogenesis by rapidly increasing capillary exchange surface area appears to be a relevant adaptive mechanism in inflammatory and ischemic tissues [23,30,31] and is characterized by pericyte detachment, increased vessel permeability and extravasation of mononuclear cells [24].…”

“…In inflammatory tissue, a shift is observed from sprouting angiogenesis toward intussusceptive angiogenesis [23]. Thus, the dynamic process of intussusceptive angiogenesis by rapidly increasing capillary exchange surface area appears to be a relevant adaptive mechanism in inflammatory and ischemic tissues [23,30,31] and is characterized by pericyte detachment, increased vessel permeability and extravasation of mononuclear cells [24]. Our data suggest that structural and architectural angioadaptations may occur in twi/twi mice in response to GALC deficiency [6,25], intussusceptive angiogenesis representing a possible mechanism of escape in the attempt to overcome defective sprouting angiogenic responses.…”

Cell behaviors and dynamics during angiogenesis

“…These indentations then grow towards each other and finally connect, forming a hollow pillar within the tube that is later invaded by pericytes and myofibroblasts. Finally, neighboring pillars fuse, resulting in longitudinal splitting of the entire vessel (Gianni-Barrera et al, 2014;Mentzer and Konerding, 2014). Intussusception is influenced by blood flow (Djonov et al, 2002), stretching (Belle et al, 2014) and signaling (Baum et al, 2010).…”