Peroxisome proliferator-activated receptor γ 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-dependent transcriptional regulation. Activation of PPAR gamma by the naturally occurring ligand, 15-deoxy-Delta 12,14-prostaglandin J(2) (15d-PGJ(2)), or members of a new class of oral antidiabetic agents, e.g. BRL49653 and ciglitizone, has been linked to adipocyte differentiation, regulation of glucose homeostasis, inhibition of macrophage and monocyte activation, and inhibition of tumor cell proliferation. Here we report that human umbilical vein endothelial cells (HUVEC) express PPAR gamma mRNA and protein. Activation of PPAR gamma by the specific ligands 15d-PGJ(2), BRL49653, or ciglitizone, dose dependently suppresses HUVEC differentiation into tube-like structures in three-dimensional collagen gels. In contrast, specific PPAR alpha and -beta ligands do not affect tube formation although mRNA for these receptors are expressed in HUVEC. PPAR gamma ligands also inhibit the proliferative response of HUVEC to exogenous growth factors. Treatment of HUVEC with 15d-PGJ(2) also reduced mRNA levels of vascular endothelial cell growth factor receptors 1 (Flt-1) and 2 (Flk/KDR) and urokinase plasminogen activator and increased plasminogen activator inhibitor-1 (PAI-1) mRNA. Finally, administration of 15d-PGJ(2) inhibited vascular endothelial cell growth factor-induced angiogenesis in the rat cornea. These observations demonstrate that PPAR gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo, and suggest that PPAR gamma may be an important molecular target for the development of small-molecule inhibitors of angiogenesis.