Biomaterial Database

Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. 1999

X Xin, and S Yang, and J Kowalski, and M E Gerritsen

Department of Cardiovascular Research, Genentech, Inc., South San Francisco, California 94080, USA.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that functions as a transcription factor to mediate ligand-dependent transcriptional regulation. Activation of PPARgamma by the naturally occurring ligand, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), 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 PPARgamma mRNA and protein. Activation of PPARgamma by the specific ligands 15d-PGJ2, BRL49653, or ciglitizone, dose dependently suppresses HUVEC differentiation into tube-like structures in three-dimensional collagen gels. In contrast, specific PPARalpha and -beta ligands do not affect tube formation although mRNA for these receptors are expressed in HUVEC. PPARgamma ligands also inhibit the proliferative response of HUVEC to exogenous growth factors. Treatment of HUVEC with 15d-PGJ2 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-PGJ2 inhibited vascular endothelial cell growth factor-induced angiogenesis in the rat cornea. These observations demonstrate that PPARgamma ligands are potent inhibitors of angiogenesis in vitro and in vivo, and suggest that PPARgamma may be an important molecular target for the development of small-molecule inhibitors of angiogenesis.

UI	MeSH Term	Description	Entries
D008024	Ligands	A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)	Ligand
D002454	Cell Differentiation	Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.	Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D002455	Cell Division	The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.	M Phase,Cell Division Phase,Cell Divisions,Division Phase, Cell,Division, Cell,Divisions, Cell,M Phases,Phase, Cell Division,Phase, M,Phases, M
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D003315	Cornea	The transparent anterior portion of the fibrous coat of the eye consisting of five layers: stratified squamous CORNEAL EPITHELIUM; BOWMAN MEMBRANE; CORNEAL STROMA; DESCEMET MEMBRANE; and mesenchymal CORNEAL ENDOTHELIUM. It serves as the first refracting medium of the eye. It is structurally continuous with the SCLERA, avascular, receiving its nourishment by permeation through spaces between the lamellae, and is innervated by the ophthalmic division of the TRIGEMINAL NERVE via the ciliary nerves and those of the surrounding conjunctiva which together form plexuses. (Cline et al., Dictionary of Visual Science, 4th ed)	Corneas
D004730	Endothelium, Vascular	Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components.	Capillary Endothelium,Vascular Endothelium,Capillary Endotheliums,Endothelium, Capillary,Endotheliums, Capillary,Endotheliums, Vascular,Vascular Endotheliums
D005786	Gene Expression Regulation	Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.	Gene Action Regulation,Regulation of Gene Expression,Expression Regulation, Gene,Regulation, Gene Action,Regulation, Gene Expression
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077154	Rosiglitazone	A thiazolidinedione that functions as a selective agonist for PPAR GAMMA. It improves INSULIN SENSITIVITY in adipose tissue, skeletal muscle, and the liver of patients with TYPE 2 DIABETES MELLITUS.	5-((4-(2-Methyl-2-(pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione-2-butenedioate,Avandia,BRL 49653,BRL-49653,BRL49653,Rosiglitazone Maleate
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia