Editorial [Hot Topic: Trends in Vascular Biology; Functional Restoration of Damaged Endothelium (Executive Editors: J.A. Rodriguez-Feo and G. Pasterkamp)]

Endothelial injury and dysfunction are early alterations in vessel wall biology preceding atherosclerotic plaque formation. In the presence of established cardiovascular risk factors, endothelial cells are constantly injured and repaired by the proliferation of resident cells and circulating endothelial progenitor cells. The maintenance of the endothelial layer physical continuity and function represents a major target for the prevention of vascular disease. This special issue covers key aspects of endothelial cell biology and potential therapeutic approaches that may restore the function of the endothelium. Basic and clinical researchers have reviewed the current state of art in endothelial dysfunction, endothelium-monocyte cross-talk, angiogenesis, arteriogenesis and the potentiality of bone-marrow derived progenitor cells to achieve a successful re-endothelization of arterial segments. The vascular endothelium is a continuous monolayer of thin, flat cells that lines the interior surface of small and large blood vessels, forming an interface between circulating blood and the subnendothelial matrix [1] (Fig. 1). Endothelial cells line the entire circulatory system, from the heart to the smallest capillary. In small blood vessels and capillaries, endothelial cells (ECs) are often the only cell-type present. For many years ECs were seen as a mere barrier that passively participated in the transport of substances from the blood to the rest of the arterial wall [1]. However, nowadays there are no doubts that the vascular endothelium acts as a key integrator and modulator of many important functions of the arterial wall (Fig. 1) [2;3]. Endothelial dysfunction is a commonly used phrase but that encompasses many different biological processes or diagnostic measures of vascular disease. Expression of selectins and integrins and subsequent enhanced monocyte adhesion, disturbed vasodilating responses and increased permeability of the endothelial layer are all features that can be observed in atherosclerotic disease and are used as a measure for endothelial dysfunction. Early in atherogenesis measures of endothelial dysfunction are detectable before other structural and/or compositional changes in the blood vessels [4]. Subsequent steps following vascular injury imply recruitment of inflammatory cells, accumulation of lipid into foam cells, oxidation of LDL, intimal growth, atherosclerotic plaque expansion and/or remodeling [5;6]. Endothelial dysfunction is a common feature in subjects suffering from diabetes mellitus, hypertension or other vascular disorders [4]. It is independently related with adverse cardiovascular events, including myocardial infarction, coronary death, and the need for revascularization. One of the main mechanisms of endothelial dysfunction is the diminishing of actions of nitric oxide (NO) [7]. The importance of NO is here documented by Braam et al. [23] who summarized several aspects regarding NO biology with a special emphasis in its numerous actions and different pharmacologic approaches leading to increase the production of endothelial-derived NO. The clinical significance and the limitations of the current methods to test endothelial functionality in human beings will be critically reviewed by Frick et al. [24]. Dysfunctional endothelial cells express more adhesion molecules and as a consequence circulating monocytes are captured by activated endothelium promoting an inflammatory reaction [8]. Monocyte adhesion to activated endothelial cells is a multistep process [5,6]. First, L-selectin and the P-selectin glycoprotein ligand-1 (PSGL-1) expressed on monocytes [7,8] and E-selectin and P-selectin expressed on activated endothelial cells [9,10] mediate the initial tethering of leukocytes, also called rolling adhesion. When a rolling monocyte encounters chemokines presented by the activated endothelial cells, integrins get activated, a process called inside-out signalling [11]. Not only chemokines, but also other stimuli like growth factors, cytokines, and bacterial-derived products such as lipopolysaccharide (LPS)3, a Toll-like receptor 4 ligand [12], and R-848, a Toll-like receptor 7 ligand [13], are able to activate integrins on monocytes. In this issue, Martin et al. [25], discuss potential pharmacological targets for the modulation of endothelial cell-monocyte cross-talk.......