Insults to endothelial cells (EC) induce a gradual response of the cell that include initially adaptation of the constitutive functions - modulation - followed by changes or impairment of cell properties - dysfunction - that may ultimately lead to cell damage - injury. To offensive factors such as hyperlipemia and hyperglycemia that cause severe alterations of plasma homeostasis, the earliest response of EC is the successive modulation of two basic functions: (i) permeability, i.e. increased transcytosis of plasma proteins, especially low density lipoproteins (LDL) and (ii) the biosynthetic, activity, i.e. enhanced synthesis of basal lamina components. Transcytosed LDL accumulates in the subendothelium, in the meshes of the hyperplasic basal lamina where they appear as physico-chemically modified and reassembled lipoproteins (MRL). At this stage, EC are afflicted on both sides: luminally by hyperlipemia and/or hyperglycemia, and abluminally by the MRL. This triggers the EC dysfunction (induction of new properties) manifested by expression of new adhesion molecules on the cell surface (E-, and P-selectins, ICAM-1, VCAM-1, and MCP-1) that binds to monocyte surface molecules (VLA-4 and CCR-2) triggering monocyte recruitment and adhesion to EC surface. Adhesion molecules together with the chemotactic effect of MRL lead to monocyte diapedesis through EC junctions and residence within the subendothelium where upon activation they become macrophages (express scavenger receptors SR-A and CD-36) take up MRL and turn into foam cells, initiating the formation of atheroma. MRL and the growth factors and cytokine produced by macrophages or lymphocytes within the subendothelium, induce migration of smooth muscle cells from the media and their proliferation in the intima; thus the EC have new cellular interactions and are exposed to new factors secreted by these cells (IFN-gamma, PDGF, TGF-beta). The new altered conditions augment the EC dysfunction, expressed by increased production of a modified extracellular matrix, prostacyclin and tromboxane A2, and a predominant procoagulant activity. At advanced stages, EC overlaying atheroma revert their net negative surface charge and become loaded with lipids (foam cells); the high concentrations of MRL, glucose and AGE-proteins are cytotoxic to EC and the protective effect of nitric oxide system becomes ineffective, leading ultimately to EC injury and apoptosis.