PlGF: a link between inflammation and angiogenesis in sickle disease

In recent years considerable evidence has accumulated that sickle cell disease is an inflammatory state. For example, sickle patients have elevated white blood counts, activated granulocytes, monocytes, and endothelial cells, enhanced expression of endothelial cell adhesion molecules, elevated cytokine levels, and elevated acute phase reactants. Neovascularization of the retina secondary to concomitant angiogenesis is a common feature of the disease. What has been puzzling is where this exuberant inflammatory response is coming from. It is unclear whether inflammation is a primary response of the polymerization of sickle hemoglobin or a secondary response to tissue injury or infection. For example, a host of speculative mechanisms for activating inflammation have been proposed, including spontaneous oxygen radical formation in the sickle red cell, reperfusion tissue injury through transient vaso-occlusion and reperfusion, activation of leukocytes by red blood cells, etc. Stated another way, how does a mutation in the beta globin gene that promotes anemia and enhanced erythropoiesis lead to an inflammatory phenotype that is proangiogenic? Two papers in this issue of Blood posit that placenta growth factor, PlGF, an angiogenic factor belonging to the vascular endothelial growth factor (VEGF) family, can be the tie that binds enhanced erythropoiesis, inflammation, and angiogenesis together in sickle cell disease. Perelman and colleagues (page 1506) demonstrate that PlGF activates monocytes, while serum levels correlate with sickle cell disease severity. Remarkably, PlGF could be induced in bone marrow CD34 progenitor cells in the presence of erythropoietin. Thus, enhanced erythropoiesis increases PlGF. In addition, PlGF increases mRNA of proinflammatory cytokines such as interleukin-1 (IL-1) and IL-8 as well as VEGF itself. In a companion manuscript by Selvaraj and colleagues on page 1515 in this issue, the mechanism of monocyte activation by PGIF is dissected. Specifically, activation of monocytes by PlGF occurs via activation of flt-1, which results in activation of PI3 kinase/AKT and ERK-1/2 pathways. PlGF levels are elevated in sickle cell disease, possibly related to chronic hypoxia. This is not surprising, since PlGF belongs to the same gene family as VEGF. This paper demonstrates that PlGF, like VEGF, signals through the flt-1 (VEGFR-1), confirming other reports. Potentially, inhibitors of flt-1 may be excellent anti-inflammatory agents for patients with sickle cell disease. There is no unifying hypothesis on how inflammation, hemoglobin polymerization, vaso-occlusion, and angiogenesis are all tied together. Is this marriage of enhanced erythropoiesis, PlGF, inflammation, and angiogenesis destined for the long term, or will it be a brief honeymoon? Studies in other hemolytic diseases and anemias and verification in animal models seem warranted.