New targets and opportunities at the level of the endothelium.

F or a single layer of cells ≈1 μm in thickness, the vascular endothelium displays an increasingly impressive array of tricks. In small arteries, complex pathways transmit vasodila-tory signals to the vascular smooth muscle layer opposing the tonic force of myogenic constriction and thus regulate blood pressure. In larger arteries, viability of the endothelium prevents atherosclerosis at sites of turbulence. Also, although not yet proven, it seems likely that endothelial health contributes to the maintenance of large vessel elasticity. As such, given the crucial role played by the endothelium in cardiovascular health, 2 recent publications from Yue et al 1,2 at the University of Illinois are particularly exciting. Their latest study 1 shows that, in cultured human umbilical vein endothelial cells, the phospholipid binding protein apolipoprotein E (ApoE) reverses the inhibitory effect of caveolin 1 on endothelial NO synthase. ApoE was derived from an exudate taken from a cultured mac-rophage colony. The interaction between ApoE and caveolin 1 underlying the functional effects on endothelial NO synthase was elucidated in 2011 when Yue et al 2 showed that ApoE colo-calized with caveolin 1 at the plasma membrane of adipocytes. The implication of the work of Yue et al 1,2 is that, in vivo, local macrophage production of ApoE may increase endothelial NO bioavailability and, thus, enhance vasodilation (in small arteries). NO release is a major component of small artery vasodi-lation and contributes ≈20% to 30% of the maximal response to acetylcholine on preconstricted arteries. More importantly, however, human studies have consistently demonstrated that it is the NO component of the endothelium-dependent dila-tion that is damaged in conditions such as diabetes mellitus 3 or obesity. 4 The capacity to modulate NO bioavailability from the endothelium is, therefore, a very attractive therapeutic opportunity. A further consideration is that macrophages influence blood vessel function not only from the luminal surface but also from perivascular sites, such as adipose tissue. 5 As such, one can easily envisage how this new pathway could potentially have major ramifications for control of vascular tone. The challenge now is to translate this novel finding from human umbilical vein endothelial cells into whole artery studies of vasodilation. This may not be as simple as it sounds. Although commercially available cultured cells are increasingly used in biomedical research, one must remember that there are major differences between cultured cells and their native counterparts. In a study of the transcriptome of both …