ICAM-2: regulator of leukocyte migration and angiogenesis

Comment on Huang et al, page 1636

In this issue of Blood, Huang and colleagues show that the endothelial adhesion molecule ICAM-2, a well-known ligand of leukocyte integrins, can mediate homophilic binding and regulate angiogenesis in various cellular assays in vitro and in vivo.

Leukocyte migration from blood into tissue is dependent on various families of adhesion molecules that mediate capturing and adhesion of leukocytes to the endothelial surface and finally the migration through the blood vessel wall. Major players in this process are the intercellular adhesion molecule-1 (ICAM-1) and ICAM-2,¹  both members of the immunoglobulin superfamily and important endothelial ligands for the leukocyte integrin lymphocyte function–associated antigen-1 (LFA-1). ICAM-1 and ICAM-2 mediate the firm adhesion and subsequent migration of leukocytes on endothelium. In addition, they are probably also involved in the transendothelial migration of leukocytes, although this is still controversially discussed. Both proteins were reported to be located at endothelial cell contacts, in addition to being expressed on the apical cell surface.

The physiologic relevance of ICAM-2 has been obscure, partly because it is the much less efficient adhesion ligand for LFA-1. Only with the analysis of gene-deficient mice did it become clear that ICAM-2 is indeed relevant for leukocyte extravasation in vivo. Lack of ICAM-2 caused a delayed increase in eosinophil accumulation in the airway lumen during the development of allergic lung disease concomitant with a prolonged accumulation of eosinophils in lung interstitium.² 

In this issue of Blood, Huang and colleagues demonstrate that endothelial ICAM-2 has yet another, hitherto unknown, function in angiogenesis. Primary isolated endothelial cells from the heart of ICAM-2–deficient mice were impaired in their ability to form tubes in vitro. In addition, matrigel plugs injected subcutaneously into these mice were less efficiently vascularized than in wild-type mice. At least in the in vitro studies, any involvement of heterophilic leukocyte ligands of ICAM-2 can be excluded as a possible molecular mechanism to explain these findings. The authors show for the first time that ICAM-2 supports homophilic interactions. Polyclonal antibodies that block this interaction could also block endothelial tube formation. This could indeed suggest a role for ICAM-2 in angiogenesis as a homophilic cell adhesion molecule. Alternatively, the polyclonal antibodies may cross-link ICAM-2 and thereby cause intracellular signals, which may interfere with the formation of tubes. Other effects that were caused by the lack of ICAM-2 were an enhanced sensitivity to apoptosis, a reduction of cell migration, and a lack of sustained Rac activation upon cell spreading.

Although it needs to be mentioned that no defects in embryonal development of ICAM-2–deficient mice have been reported, suggesting that ICAM-2 is not essential for blood vessel formation in the embryo, it is possible that a function of ICAM-2 during embryonal angiogenesis is redundant and detectable only in the adult organism. Other homophilic adhesion mechanisms exist at endothelial junctions that are relevant for angiogenesis. The endothelial cell-selective adhesion molecule (ESAM) at endothelial tight junctions is involved in tumor angiogenesis, yet ESAM-deficient mouse embryos develop normally.³  A major adhesive mechanism at endothelial contacts, essential for angiogenesis in the embryo, is vascular endothelial (VE)–cadherin.^4,5  Lack of VE-cadherin increased endothelial apoptosis, yet additional functions are conceivable that may affect blood vessel stability.

The work by Huang and colleagues illustrates that the repertoire of adhesive mechanisms at endothelial cell contacts that are participating in the formation of blood vessels might be complex. ▪