In contrast to
VEGF and its receptor
VEGFR-2, PlGF and its receptor
VEGFR-1 have been largely neglected and therefore their potential for
therapy has not been previously explored. In this review, we describe the molecular properties of PlGF and
VEGFR-1 and how this translates into an important role for PlGF in the angiogenic switch in
pathological angiogenesis, by interacting with
VEGFR-1 and synergizing with
VEGF. PlGF was effective in the growth of new and stable vessels in cardiac and limb
ischemia, through its action on different cell types (i.e. endothelial, smooth muscle and inflammatory cells and their precursors) that play a cardinal role in blood vessel formation. Accordingly, blocking its receptor
VEGFR-1 with
monoclonal antibodies (anti-VEGFR-1 mAb), expressed on al these cell types, successfully attenuated blood vessel formation during
cancer, ischemic retinopathy and
rheumatoid arthritis. In addition, while blocking this receptor was effective in reducing inflammatory disorders like
atherosclerosis and
rheumatoid arthritis, blocking the anti-angiogenic receptor
VEGFR-2 was without effect. This indicates that in the latter diseases the beneficial effects of anti-VEGFR1 mAb were mainly due to its effect on inflammatory cells. Importantly,
VEGFR-1 was also present on hematopoietic stem/progenitor cells, the precursors of inflammatory cells. Thus, these preclinical studies show proof-of-principle that PlGF and
VEGFR-1 are promising therapeutic targets to treat angiogenesis and
inflammation related disorders. Clinical trials will reveal whether this is also true for patients.