Topographische und klinische Anatomie
The concept of intussusceptive angiogenesis
The research projects of our group are focused on vascular morphology and intussusceptive angiogenesis during development, tissue repair and carcino-genesis. Non-sprouting angiogenesis by intussusception was first observed by Prof. Peter Burri in our group (Caduff et al. 1986). The authors postulated that the pulmonary capillary networks of neonatal rat expanded predominantly by insertion of transcapillary tissue pillars, a phenomenon that had hitherto not been described. They coined the term “intussusceptive microvascular growth” for this process, thereby implying that the capillary network expanded “within itself”.
A transluminal tissue pillar, the hallmark of intussusceptive angiogenesis (IA), is formed by simultaneous intraluminal invagination of opposing sides of the capillary wall and establishment of contact between the endothelial protrusions. After perforation of the contact zone, the pillar core is invaded first by pericytes and then by connective tissue and parenchymal cells
The outcomes of intussusceptive angiogenesis
Intussusception is involved in vascular remodelling processes, which have different morphological and functional outcomes. Firstly, sporadic occurrence of pillars within the capillary bed leads to an expansion of the latter and an increase in its complexity, namely, to Intussusceptive Microvascular Growth (IMG). Secondly, pillars may arise in series and then merge to form small arteries and veins in distal parts of the vascular tree, thus leading to Intussusceptive Arborization (IAR). Thirdly, pillar formation occurring within small arteries and veins can lead to remodelling, an optimization of the branching geometry and of the haemodynamics of the vascular tree, namely, to Intussusceptive Branching Remodelling (IBR).
Our recently obtained data indicate that IA is essential for formation and restoration of an organ-specific angioarchitecture (Makanya et al., 2009; Wnuk et al., Am J Path, 2011). In addition, IA plays an important role as an “escape” mechanism (Fig. 1) during and after irradiation and anti-VEGF therapy (Hlushchuk et al., Am J Path, 2008). Both treatments induced angiogenic switch from sprouting to IA (Fig. 1) by formation of multiple transluminal tissue pillars in the enlarged sinusoidal-like vessels. Up-regulated α-SMA-expression observed in the later stages actively of treatment plausibly reflected recruitment and differentiation of precursor cells as part of pillar formation and increased vessel coverage with periendothelial cells. Preliminary data obtained from cancer patients indicate that the switch from sprouting to IA could represent an escape mechanism also in humans (cancer patients) accounting for the development of resistance to antiangiogenic treatment.
The regulatory mechanisms of the intussusceptive angiogenesis
The regulatory mechanisms of intussusception are not yet well characterized. However, there are strong indicators for interplay between molecular pathways and hemodynamic forces.
- Molecular pathways: It is gradually becoming clearer that intussusception is synchronized by several cytokines, mediating information between endothelial cells (ECs) or ECs to mural cells – such as PDGF-BB/PDGFR-β, TGF-β, monocyte chemotactic protein-1, ephrins/Eph-receptors etc. Our recent observations point to the possibility that Notch inhibition destroys vessel integrity by disturbing maturation and alignment of pericytes, a phenomenon associated with increased vessel permeability. This effect is followed by invasion of incipient pillars by mononuclear cells. The latter cells, thus actively participate in the process of intussusceptive vascular growth.
- Haemodynamic forces: This far, little is known regarding the impact of hemodynamic forces on intussusception. Using an in vitro approach by means of flow chamber and in vivo experiments in different animal models we aim to estimate the role of shear stress and circumferential wall stress on intussusceptive angiogenesis.