Vascular endothelial cells contribute to the release of protective mediator in large blood vessels, where endothelial damage or dysfunction is considered one of the potential mechanisms for development of atherosclerosis and restenosis (see Drexler & Hornig, 1999). In the microvasculature, the endothelium contributes to chronic inflammatory processes, wound healing, and tumour formation by an angiogenic response, vascularizing the newly produced tissue (Folkman, 1995). Vascular endothelial cells contain PPARα (Inoue et al., 1998; Xin et al., 1999; Bishop-Bailey & Hla, 1999), PPARδ (Xin et al., 1999; Bishop-Bailey & Hla, 1999), and PPARγ (Marx et al., 1999a; Xin et al., 1999; Bishop-Bailey & Hla, 1999), though, as yet no definitive roles for PPARδ have been described. PPARα agonists, similar to their effects in vascular smooth muscle cells inhibit NF-κB signalling, by which mechanism they can inhibit TNF-α induced expression of vascular cell adhesion molecule-1, and the subsequent adherence of monocytes (Marx et al., 1999b). Like other cell types PPARγ appears to have both potential protective and detrimental effects. In terms of large vessel disease, PPARγ activators inhibit the endothelial cell release of endothelin-1 (Satoh et al., 1999; Delerive et al., 1999), a potent vascoconstrictor, and vascular smooth muscle cell mitogen (see Ruschitzka et al., 1997). In contrast, PPARγ agonists also increase plasminogen activator inhibitor (PAI)-1 expression (Marx et al., 1999a; Xin et al., 1999). PAI-1 is highly expressed in adipocytes, and levels correlate with obesity, furthermore, increased PAI-1 is associated with myocardial ischaemia, and thrombosis (Loskutoff & Samad, 1997). A role which is unsurprising since PAI-1 inhibits two of the enzymes which play a major role in fibrinolysis, tissue plasminogen activator and urokinase. The reverse side to the inhibition of PAI-1 in large vessels, is that in small vessels increasing PAI-1 (Xin et al., 1999) may be one of the mechanisms responsible for inhibition of angiogenesis by PPARγ agonists (Xin et al., 1999; Bishop-Bailey & Hla, 1999). Furthermore, PPARγ agonists also reduce the vascular endothelial cell growth factor receptors Flt-1, and Flk/KDR, and inhibit the expression of urokinase (Xin et al., 1999). Alternatively, PPARγ activators can inhibit endothelial cell angiogenesis by inducing apoptosis (Bishop-Bailey & Hla, 1999), similar to macrophages (Chinetti et al., 1998), via a caspase-3 mediated process. Though again in contrast to the microvasculature, in a large vessel disease, inappropriate apoptosis may cause structural weakness in an atherosclerotic lesion, and may promote plaque rupture (Newby & Zaltsman, 1999), which may lead to embolism or stroke.
In the microvasculature PPARγ may be a novel target for anti-angiogenic therapy for a number of tumours or chronic inflammatory disorders. Like other cells, PPARγ activation can inhibit cytokine induced mediator release, which may be beneficial in large vessel disease. Many of the effects described which would be beneficial in the microvasculature however, inhibiting endothelial cell function, may naturally be detrimental to protecting against atherogenic stimuli.