Blood-vessel formation: Bridges that guide and unite
Nature 465, 697–699 (10 June 2010)
To form new blood vessels, the endothelial tip cells of two existing vessels come together by the process of anastomosis. But how do they find each other? Macrophages seem to provide a bridge and mediate their union.
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Many primitive organisms lack blood vessels, and oxygen simply diffuses to their innermost cells. Blood vessels arose in evolution when organisms outgrew the physical limits of oxygen diffusion. They are lined with endothelial cells and branch by sprouting — sending out specialized endothelial cells called tip cells at the forefront of the sprout that navigate to their target1. Previous studies have mainly focused on understanding how tip cells initiate vessel sprouting; so nearly nothing is known about how these cells fuse with neighbouring sprouts to form a perfused vessel. Writing in Blood, Fantin et al.2 report that, contrary to expectation, tip cells lack the precision to find, recognize and fuse with other tip cells. Instead, macrophages, phagocytic cells of the immune system, serve both as what we would like to call 'bridge cells' and as guidance posts to precisely position tip cells in preparation for accurate fusion.Fantin and co-workers show that, precisely when tip cells are about to fuse — a process referred to as anastomosis — tissue-resident macrophages are located in the vicinity of vessel branches. Further, the absence of macrophages or blockage of their function impairs vessel fusion and thereby angiogenesis, the formation of new vessel circuits (Fig. 1, overleaf). For aficionados in the field who had expected that tip cells would perform this job without external help, these findings not only shed light on a fundamental aspect of angiogenesis, but also highlight the growing evidence for a link between macrophages and angiogenesis.
During vessel branching, endothelial tip cells migrate in response to a VEGF gradient. a, As guidance posts, macrophages act as bridge cells to assist tip cells and provide precision in preparation for the fusion of these specialized endothelial cells. Once the tip cells come together by the process of anastomosis, the fused vessel becomes perfused with blood and the tip cells acquire a quiescent phalanx-cell-type phenotype. b, In the absence of bridge macrophages, the emerging branches lack precision for the fusion process and remain separate, thereby leading to defective blood-vessel fusion and a reduced complexity of the vascular network.
Indeed, macrophages can regulate the growth and remodelling of blood and lymph vessels in quite different ways. As their name (Greek for 'big eater') reflects, they can inhibit angiogenesis by initiating a cell-death program in endothelial cells and engulfing the dying cells3, and they can also inhibit angiogenesis more generally; the macrophages that carry out these processes are of the type termed M1 (ref. 4). Another type of macrophage, called M2, promotes angiogenesis by releasing pro-angiogenic factors such as VEGF and VEGF-C, and thereby induces tip-cell formation4, 5. The macrophages that Fantin and colleagues describe are polarized towards the M2 type.
Disease is another setting in which macrophages affect vessel formation. In tumours, they excessively stimulate angiogenesis, leading to abnormal vessels that function poorly6. Other myeloid cells — the class of bone-marrow-derived cells to which macrophages belong — can also be recruited to tumours to mediate tumour escape from anticancer therapies that inhibit VEGF; the myeloid cells overcome the effects of anti-VEGF therapy by releasing other angiogenic signals7. In certain circumstances, macrophages can even differentiate into endothelial cells. In other cases, by locally producing growth factors and protease enzymes, macrophages fuel the enlargement of collateral vessels in ischaemic tissues, which have a restricted blood supply.
In none of these previous reports were myeloid cells implicated in tip-cell anastomosis or vessel fusion. But a link between immune-system cells and endothelial cells is not so surprising. In evolution, blood vessels first arose as channels with no endothelial-cell lining, along which macrophages patrolled to carry out immune surveillance8. This may also explain why VEGF attracts macrophages in mammals and haemocytes, ancestors of macrophages, in fruitflies.
Remarkably, Fantin and colleagues' finding that tissue macrophages serve as both bridge cells and guidance posts to properly position the budding vessel branches is reminiscent of how, in the fruitfly, cell clusters in the insect's developing tracheal system (the insect airway) connect by fusion. Just as endothelial tip cells use filopodial projections to explore their environment, tracheal tip cells project filopodium-like cell extensions to fuse with their partner. These extensions connect with, and slide along, the surface of a specialized bridge cell that helps to correctly position both tracheal-cell partners in preparation for fusion9. Just as macrophages use filopodia to pull pathogens towards themselves10, perhaps 'bridge' macrophages also use filopodia to pull endothelial tip cells towards the meeting point.
Bridge-cell recognition, filopodial sliding and the fusion of airway epithelial cells in the fruitfly have all been proposed to rely on the extracellular matrix and cell-adhesion molecules on the surface of both the bridge cell and the fusing cells. Bridge cells in fly airways release fibroblast growth factor, which acts as a short-range guidance signal to attract and position the filopodia of tracheal cells9. Also, the adhesion molecule VE-cadherin regulates fusion between endothelial cells of vessel branches11. Intriguingly, low levels of VE-cadherin are also expressed in macrophages, raising the question of whether this molecule promotes the 'zipping' of tip cells with macrophage bridge cells5.
Tissue-resident macrophages are motile cells, swiftly navigating deep into the tissue. The shortage of oxygen in such situations could help them to zoom in on sites of vessel fusion, although it remains a mystery how they recognize the endothelial tip cells that are about to fuse. Macrophages express Notch receptors and tip cells express Dll4 — a ligand that activates Notch; the question therefore arises whether such paracrine (to adjacent cells) signalling is involved in bringing the two cell types together. Macrophages also express the Tie2 receptor, so perhaps its ligand, angiopoietin-2, expressed in tip cells12, is another guidance candidate.
As VEGF favours the development of tip-cell properties, it is not surprising that Fantin et al.2 find that VEGF is not required for endothelial-cell fusion. Instead, VEGF participates in other steps of tubule formation (tubulogenesis), in which its role is conserved from the gastro-vascular system in jellyfish to mammalian vascular and neuronal systems. What's more, bridge macrophages could release signals that alter the differentiation of endothelial cells in preparation for fusion. Indeed, cell differentiation and tubulogenesis are closely linked13, and to form a stable, perfused vessel, tip cells must adopt a more quiescent phenotype similar to that of the cells in the bulk of the vessel (the 'phalanx' cell type)14 (Fig. 1).
As is often the case with findings that break new ground, Fantin and colleagues' observations raise questions about the underlying molecular mechanisms and have possible medical implications. For instance, what is the precise molecular signature of the M2 macrophage bridge cells? How do they home in to sites of vessel fusion and recognize anastomosing tip cells? And what signals do they use to attract endothelial filopodia and position them correctly for fusion?
Are macrophages also involved in vessel fusion in tumours? If they are, then why are so many vessels in tumours chaotically disordered (perhaps improperly fused)? After all, tumours contain numerous macrophages. Will vessel branches that fail to fuse keep wandering around or will they regress and die? Can the signals that bridge cells use to mediate fusion also be exploited for stimulating revascularization of ischaemic tissues? Conversely, can they be blocked to inhibit tumour angiogenesis? Answering these and related questions promises an exciting exploration of blood-vessel formation for years to come.
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