Increased permeability of, and bleeding from, microvessels within the atheromatous arterial wall participate in atherothrombosis progression. The VEGF family and angiopoietin system components govern microvessel development and maturation. Serine protease activities are proportional to atherothrombosis progression and linked to intraplaque hemorrhage. Here we investigated the relationship between angiogenic factors and proteases in human hemorrhagic and non-hemorrhagic atheromatous carotid samples by immunohistochemistry, in situ hybridization and ELISA. Plaque activity of plasmin and leukocyte elastase and proteolysis of angiogenic factors by plaque extracts were determined. Smooth muscle cell migration induced by hemorrhagic and nonhemorrhagic plaques was assessed. The absence of á-actin-positive cells characterized microvessels in hemorrhagic areas in spite of similar expression of VEGF and angiopoietin system components in microvessels of hemorrhagic and non-hemorrhagic areas. However, VEGF, PlGF and angiopoietin-1 levels were signifi cantly decreased in hemorrhagic compared to non-hemorrhagic plaques, whereas angiopoietin-2 did not change and soluble Tie-2 levels increased. Consequently, smooth muscle cell migration stimulatory activity of hemorrhagic plaques was reduced. Recombinant PlGF, VEGF and angiopoietin-1 added to plaque extracts were only degraded by hemorrhagic lesions. This proteolysis was prevented by inhibitors of plasmin and elastase, whose activity was increased in hemorrhagic plaques. No degradation was observed for angiopoietin-2. Decreased angiogenic factor levels caused by proteolysis may destabilize plaque microvessels via impairment of mural cell recruitment, thus leading to a vicious circle of intraplaque hemorrhages and lesion progression.