multiple injurious stimuli to the Endothelium, intima, media, and adventitia. The endothelial cell is exposed to multiple injurious stimuli consisting of: modified LDL-cholesterol, various infection insults (viral and bacterial), angiotensin II, hemodynamic stress, LPa, glucose, homocysteine, uric acid, Ca++, phosphorus, parathyroid hormone, and intimal redox stress or reactive oxygen species. These multiple injurious stimuli (A-FLIGHT-U) cause a chronic injury and a response to injury with resultant remodeling of the arterial vessel wall and in particular the ECM. In the MetS, prediabetes, and overt T2DM, these stimuli act in concert to result in this detrimental remodeling with structural-functional abnormalities and dysfunction. The endothelium and its BM act as the first line of defense and are therefore the first cell and matrix to be affected with resulting dysfunction and structural changes. MetS, prediabetes, and T2DM undergo an accelerated atherosclerosis we term atheroscleropathy. Oxidation, glycation, glycoxidation, or homocysteinylation must modify LDL-cholesterol for LDL-C to become atherogenic. Multiple injurious stimuli acting alone and synergistically to modify LDL-cholesterol with resultant matrix structural defects accelerating atherogenesis and angiogenesis are observed. Each layer of the arterial vessel wall is eventually affected by these injurious stimuli initially from the lumen outward (inside-out) and later in the process to effect the plaque vulnerability from the outside-in (adventitial layer) by an inducible set of custom delivery vessels called the vasa vasorum.