PPARgamma is a member of a family of nuclear receptors/ligand-dependent transcription factors, which bind to hormone response elements on target gene promoters. An antiproliferative and proapoptotic action profile of PPARgamma has been described and PPARgamma may function as a tumor suppressor gene, but little is known about the role of PPARgamma in vascular remodeling. One group of human diseases that shows impressive vascular remodeling exclusively in the lungs is the group of severe pulmonary hypertensive disorders, which is characterized by complex, endothelial cell-proliferative lesions of lung precapillary arterioles composed of clusters of phenotypically altered endothelial cells that occlude the vessel lumen and contribute to the elevation of the pulmonary arterial pressure and reduce local lung tissue blood flow. In the present study, we report the ubiquitous PPARgamma expression in normal lungs, and in contrast, a reduced lung tissue PPARgamma gene and protein expression in the lungs from patients with severe PH and loss of PPARgamma expression in their complex vascular lesions. We show that fluid shear stress reduces PPARgamma expression in ECV304 endothelial cells, that ECV304 cells that stably express dominant-negative PPARgamma (DN-PPARgamma ECV304) form sprouts when placed in matrigel and that DN-PPARgamma ECV304 cells, after tail vein injection in nude mice, form lumen-obliterating lung vascular lesions. We conclude that fluid shear stress decreases the expression of PPARgamma in endothelial cells and that loss of PPARgamma expression characterizes an abnormal, proliferating, apoptosis-resistant endothelial cell phenotype.