Once the epithelial injury occurs and causes the endothelial cells to become inflamed, they then lack the ability to produce sufficient amounts of antithrombotic and vasodilating cytokines. Macrophages and platelets adhere to the area of injury in the endothelium and toxic oxygen radicals are released by the macrophages. Platelets further stimulate the inflammatory response. Toxic oxygen radicals create oxidative stress and oxidize LDL. This causes additional endothelial damage. Growth factors (angiotensin II, fibroblast growth factor, TGF-β, and platelet derived growth factor) are released which cause smooth muscle hyperplasia. LDL penetrates the subintima of the vessel and becomes trapped and is oxidized by the above process. Oxidized LDL is toxic and causes smooth muscle proliferation (hyperplasia). It also increases endothelial adhesion molecule expression which results in the adhesion of more macrophages which penetrate the vessel wall. The macrophages then engulf the LDL, and they are then known as foam cells. The accumulation of the foam cells increases over time and causes a fatty streak. The fatty streak produces more toxic oxygen radicals, triggers more of an immune and inflammatory response, all of which causes ongoing, progressive damage to the vessel. Smooth muscle hyperplasia is ongoing, produces collagen and migrates over the fatty streak to form a fibrous plaque. This plaque may calcify, protrude in the vessel lumen and occlude flow. Plaques can be unstable and may rupture secondary to inflammatory activations and acutely occlude blood flow and result in ischemia or infarction.