Abstract
Intussusceptive angiogenesis (IA) is a complementary method to sprouting angiogenesis (SA). The hallmark of IA is formation of trans-capillary tissue pillars, their fusion and remodeling of the vascular plexus. In this study, we investigate the formation of the zebrafish caudal vein plexus (CVP) in Tg(fli1a:eGFP)y7 and the synergistic interaction of IA and SA in crafting the archetypical angio-architecture of the CVP. Dynamic in vivo observations and quantitative analyses revealed that the primitive CVP during development was initiated through SA. Further vascular growth and remodeling occurred by IA. Intussusception contributed to the expansion of the CVP by formation of new pillars. Those pillars arose in front of the already existing ones; and in a subsequent step the serried pillars elongated and fused together. This resulted in segregation of larger vascular segments and remodelling of the disorganized vascular meshwork into hierarchical tree-like arrangement. Blood flow was the main driving force for IA, particularly shear stress geometry at the site of pillar formation and fusion. Computational simulations based on hemodynamics showed drop in shear stress levels at locations of new pillar formation, pillar elongation and fusion. Correlative 3D serial block face scanning electron microscopy confirmed the morphological substrate of the phenomena of the pillar formation observed in vivo. The data obtained demonstrates that after the sprouting phase and formation of the primitive capillary meshwork, the hemodynamic conditions enhance intussusceptive segregation of hierarchical vascular tree i.e. intussusceptive arborization resulting in complex vascular structures with specific angio-architecture.
Highlights
Intussusceptive angiogenesis (IA) is a complementary method to sprouting angiogenesis (SA)
After 36 hpf, expansion of the caudal vein plexus (CVP) was mainly driven by formation of intussusceptive pillars, which were mostly observed in the proximal perfused region (Fig. 2C) while the angiogenic sprouts drove vascular growth in the distal non-perfused region of the CVP (Fig. 2B)
At the same time the latter should adapt to the changing hemodynamic conditions i.e. increased blood pressure and blood velocity
Summary
Intussusceptive angiogenesis (IA) is a complementary method to sprouting angiogenesis (SA). Intussusceptive arborization entails formation and subsequent fusion of serried pillars delineating straight capillary segments and generations of smaller future feeding and draining microvessels By this process, fusing pillars allocate hierarchical microvascular segments restructuring the primitive capillary meshwork to a vascular tree. Optimization of local vascular branching geometry occurs through intussusceptive branching remodelling, so that the vasculature is remodelled to meet the local hemodynamic demand The latter process occurs via transluminal pillars that are formed close to arterial or venous bifurcation sites. One of the main differences between sprouting and intussusceptive angiogenesis is that sprouts appear (initially) in regions lacking perfusion, whereas pillars are formed in the perfused vascular areas[15,16,17,18,19,20] These observations clearly point towards a significant role of blood flow and shear stress mediating intussusceptive vessel splitting. There is no single mechanotransducer clearly linked to IA, but several mechanosensing biological components, which could potentially regulate blood flow-driven pillar formation, have been documented[21]
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