In this paper, Fiedler and colleagues discovered a surprising function for the anti-angiogenic protein angiopoietin-2 (ang2) - modulation of the inflammatory response. Mice rendered genetically null for ang-2 had dramatically diminished ability to recruit neutrophils into their peritoneal cavities after a potent local pro-inflammatory challenge despite normal circulating white blood cell counts. Using the powerful tool of in vivo video microscopy to monitor the vascular component of the inflammatory response, they found that leucocytes in ang-2 null mice exhibited a steady increase in "rolling" down the inner wall of cutaneous blood vessels superfused with the pro-inflammatory cytokine TNF-α, but diminished ability to stick firmly to the endothelium. This indicates that the leukocytes could "sense" the presence of inflammation (i.e., tether and roll down the endothelial lining), but were unable to adhere firmly enough to migrate through the vessel wall and enter the inflamed tissues. What exactly is ang-2 doing in this setting? Previous studies showed that vascular endothelial cells (EC) store ang-2 in granules that are released in response to pro-inflammatory or pro-thrombotic stimuli, including TNF-α. The investigators therefore "knocked down" expression levels of endogenous ang-2 in cultured human EC and showed that adhesion molecule expression in response to low concentrations of TNF-α was abrogated. Furthermore, they showed that exposing exogenous ang-2 by itself to EC did not affect leukocyte adhesion, but significantly enhanced adhesion if the EC were co-treated with small amounts of TNF-α.
In Brief
Angiogenesis, both embryonic and postnatal, is controlled by a complex signaling network involving factors that regulate growth, migration, and remodeling of nascent blood vessels. An important component of this network is tie-2, a tyrosine kinase receptor on the surface of EC that responds to two related proteins known as angiopoietins. Ang-1 is secreted by peri-vascular smooth muscle cells (pericytes) in a paracrine manner and provides crucial maturation signals to stabilize neo-vessels. Ang-2 is produced by EC in an autocrine manner and was initially thought to serve as an antagonist to ang-1 signaling, leading to capillary disruption. More recently it has been shown that in some vessels, particularly lymphatic, ang-2 has a tie-2-dependent agonist function. Mice with genetic deletion of angiopoietins or tie-2 have severe vascular developmental defects. This paper points to an important role for the angiopoietin system in inflammation as well as angiogenesis. The data suggest that ang-2 "primes" or sensitizes EC to respond to subthreshold concentrations of TNF-α, thereby amplifying the developing inflammatory response. The mouse experiments show that this amplification step is crucial for initiating a sustained inflammatory response. Thus ang-1 and ang-2 seem to function through tie-2 as binary switches to stabilize (ang-1) or destabilize (ang-2) blood vessels and amplify (ang-2) or inhibit (ang-1) inflammation. This cross talk between inflammatory signaling and angiogenic signaling is not altogether surprising given the importance of new vessel formation in certain types of inflammation (e.g., wound granulation tissue). Furthermore, studies of unrelated systems, such as obesity and insulin resistance, revealed that inflammatory signaling pathways are actually critically connected to other seemingly unrelated signaling systems via "cross talk" among receptors and downstream effectors. These studies point to novel pathways other than TNF-α to target for anti-inflammation drug development.
Competing Interests
Dr. Silverstein indicated no relevant conflicts of interest.
