Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor that functions as a transcription factor to mediate ligand-depende nt transcriptional regulation. Activation of PPAR gamma by the naturally oc curring ligand, 15-deoxy-Delta 12,14-prostaglandin J(2) (15d-PGJ(2)), or me mbers of a new class of oral antidiabetic agents, e.g. BRL49653 and cigliti zone, has been linked to adipocyte differentiation, regulation of glucose h omeostasis, inhibition of macrophage and monocyte activation, and inhibitio n of tumor cell proliferation. Here we report that human umbilical vein end othelial cells (HUVEC) express PPAR gamma mRNA and protein. Activation of P PAR gamma by the specific ligands 15d-PGJ(2), BRL49653, or ciglitizone, dos e dependently suppresses HUVEC differentiation into tube-like structures in three-dimensional collagen gels. In contrast, specific PPAR alpha and -bet a ligands do not affect tube formation although mRNA for these receptors ar e expressed in HUVEC. PPAR gamma ligands also inhibit the proliferative res ponse of HUVEC to exogenous growth factors. Treatment of HUVEC with 15d-PGJ (2) also reduced mRNA levels of vascular endothelial cell growth factor rec eptors 1 (Flt-1) and 2 (Flk/KDR) and urokinase plasminogen activator and in creased plasminogen activator inhibitor-1 (PAI-1) mRNA. Finally, administra tion of 15d-PGJ(2) inhibited vascular endothelial cell growth factor-induce d angiogenesis in the rat cornea. These observations demonstrate that PPAR gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo, a nd suggest that PPAR gamma may be an important molecular target for the dev elopment of small-molecule inhibitors of angiogenesis.