Atherosclerosis is now generally accepted as an inflammatory disease, characterized by degenerative changes and extracellular accumulation of lipid and cholesterol. The evolving inflammatory reaction plays an important role in the initiation of atherosclerotic plaques and their destabilization, converting a chronic process into an acute disorder with an ensuing thrombo-embolism. Neovascularization has been, also, recognized as an important process for the progression of atherosclerotic plaques. In fact, vulnerable atherosclerotic plaque prone to rupture are characterized by an enlarged necrotic core containing an increased number of vasa vasorum, apoptotic macrophages, and more frequent intraplaque haemorrhage. Various functional roles have been assigned to intimal microvessels. This network of immature blood vessels is a viable source of intraplaque haemorrhage providing erythrocyte-derived phospholipids and free cholesterol. However, it is still challenging and controversial the relationship between the very process of angiogenesis and its causal association with the progression and complication of atherosclerosis. The selective targeting of neoangiogenesis poses a possible approach for the elimination of pre-existing and new growth of microvessels. The identification of target lesions is a critical issue, because current technologies have yet to achieve the goal of characterizing plaque morphology to the degree necessary to correctly identify rupture-prone lesions according to pathologic criteria. However, few imaging techniques can be used to detect the neovascularization within the atherosclerotic plaque in vivo. This review discusses the potential role of intraplaque angiogenesis as risk factor for plaque vulnerability.

Histone deacetylases (HDAC) are key enzymes in the epigenetic control of gene expression. Recently, inhibitors of class I and class II HDAC have been successfully employed for the treatment of different inflammatory diseases such as rheumatoid arthritis, colitis, airway inflammation and asthma. So far, little is known so far about a similar therapeutic effect of inhibitors specifically directed against sirtuins, the class III HDAC. In this study, we investigated the expression and localization of endogenous sirtuins in primary human dermal microvascular endothelial cells (HDMEC), a cell type playing a key role in the development and maintenance of skin inflammation. We then examined the biological activity of sirtinol, a specific sirtuin inhibitor, in HDMEC response to pro-inflammatory cytokines. We found that, even though sirtinol treatment alone affected only long-term cell proliferation, it diminishes HDMEC inflammatory responses to tumor necrosis factor (TNF)α and interleukin (IL)-1β. In fact, sirtinol significantly reduced membrane expression of adhesion molecules in TNFã- or IL-1β-stimulated cells, as well as the amount of CXCL10 and CCL2 released by HDMEC following TNFα treatment. Notably, sirtinol drastically decreased monocyte adhesion on activated HDMEC. Using selective inhibitors for Sirt1 and Sirt2, we showed a predominant involvement of Sirt1 inhibition in the modulation of adhesion molecule expression and monocyte adhesion on activated HDMEC. Finally, we demonstrated the in vivo expression of Sirt1 in the dermal vessels of normal and psoriatic skin. Altogether, these findings indicated that sirtuins may represent a promising therapeutic target for the treatment of inflammatory skin diseases characterized by a prominent microvessel involvement.