What is Intussusceptive Angiogenesis
Much of the research on angiogenesis has focused on one type, Sprouting Angiogenesis (SA). Initially, the discovery of another type called Splitting or Intussusceptive Angiogenesis (IA) did not cause a stir as it was believed to operate under the same mechanisms as SA. However, recent discoveries have shown that these are two complementary processes and the distinction between the two is crucial especially in terms of treatment.
Whereas the importance of SA has been established for vascular growth, Intussusceptive Angiogenesis seems to play a role in remodeling existing and new vascular beds made by SA. The most characteristic feature of IA is the formation of the transluminal pillar (2). This pillar is what divides the lumen of an existing blood vessel ultimately dividing it into two. The process of pillar formation starts with the migration of opposing endothelial walls within a vessel, followed by rearrangements of interendothelial junctions and invasion of pericytes and myofibroblasts, consequently leading to the splitting of the vessel (1). IA can then be further classified into three different forms depending on the phenotypic outcome. The altered vascular plexus could be a result of intussusceptive microvascular growth (IMG), intussusceptive arborization (IAR), and/or intussusceptive branching remodeling (IBR) (1).
Mechanisms that drive IA
Hemodynamic forces are suggested to be the driving force behind IA. An experiment using chick chorioallantoic membrane (CAM) showed that an increase in blood flow led to increase in IA (1). Studies involving silico models have shown that shear stress also plays a role due to its effect on the level of blood flow (1). According to the Styp-Rekowska et al. (4) angioadaptive processes are largely predetermined by patterning genes but the effect of biomechanical forces are not to be undermined. Styp-Rekowska et al. (4) identifies the mechanical forces acting upon the endothelial cells that line the insides of blood vessels as hydrostatic pressure, cyclic stretch, and shear stress all caused by blood pressure, vessel deformation, and blood flow respectively.
Angiogenic factors such as VEGF have also been proposed to affect IA. Although unclear, it seems that some VEGF isoforms are upregulated or downregulated at certain periods of glomerular growth (1). Angiopoietins and fibroblast growth factors also appear to coincide with the switch from SA to IA (1). Similar to SA, hypoxia also seems to upregulate IA. Erythropoietin (EPO), whose expression is upregulated by hypoxia inducible factors, is proposed to be a possible regulator of IA (1). Overall, more studies are needed to further understand and determine the interacting factors leading to the IA process. For now it seems that shear stress levels favors IA whereas angiogenic factors in response to hypoxic conditions seem to favor SA (4).
The Angiogenic Switch from Sprouting to Intussusception
There seems to be a temporal relationship between SA and IA, with SA initially preceding IA and then IA ultimately displacing it (4). In both cases, SA was seen to be responsible for the early stages of angiogenesis but IA subsequently predominates in the fine tuning of this system (1). The process of IA has been observed in developing glomeruli and in cyclic ovary. The complementation between SA and IA has also been observed in the development of chicken lung, with SA establishing the vessels first followed by IA which expands and aids in their maturation (2). While present in normal physiological conditions, the process of IA has also been shown to be involved in pathological cases, one of which is on tumor growth.
The distinction between these two processes, SA and IA, is highlighted in tumor angiogenesis where the rapid recovery of tumors following anti-angiogenic treatments or radiotherapy was reported to result from the switch of SA to IA (2). This finding is crucial for therapeutic purposes. Several factors such as angiogenic factors, oxygen availability, and hemodynamic conditions determine whether SA or IA will occur (4). This indicates that, in addition to anti-angiogenic drug therapy that halts SA, specifically targeting factors involved in the induction of IA could be a potential target to more effectively hamper angiogenesis in tumor growth. In a study conducted by Hlushchuk, et al. (3) tumor recovery was linked to the tumor’s ability to switch from sprouting to intussusceptive angiogenesis. Mammary carcinoma allografts were given either radiation therapy (ionizing radiation) or anti-angiogenic/anti-VEGF therapy (vascular endothelial growth factor tyrosine kinase inhibitor PTK787/ZK222854)v(3). It was found that in both types of therapy, tumor vasculature was indeed reduced but the effects only lasted for a short while. Immediately after cessation of treatment, a switch occurred from sprouting angiogenesis to intussusceptive angiogenesis. This switch was characterized by morphological changes, normalizing the tumor vasculature, serving as an angio-adaptive mechanism (3).
Several advantages are associated with the switch between the two types of angiogenesis. First, intussusceptive angiogenesis generates blood vessels in a more rapid fashion; second, it is more efficient in terms of the use of energy and metabolism; and third, the capillaries formed from this process are sturdier and less leaky (3). The process of IA occurs at a much faster rate than SA and it is more energy efficient because basal membrane degradation and invasion processes are not required unlike in SA (5). Overall, the process of intussusceptive angiogenesis is an adaptive response allowing the tumor to re-establish its vascular system. After that, a second wave of sprouting angiogenesis occurs along with tumor re-growth. This whole process of vascular remodeling allows the tumor to recover from the treatment and eventually develop resistance to therapy (3).