α ₂ -Antiplasmin Gene Deficiency in Mice Does Not Affect Neointima Formation After Vascular Injury

Abstract

Abstract-The hypothesis that ␣ 2 -antiplasmin (␣ 2 -AP), the main physiological plasmin inhibitor, plays a role in neointima formation was tested with use of a vascular injury model in wild-type (␣ 2 -AP ϩ/ϩ ) and ␣ 2 -AP-deficient (␣ 2 -AP Ϫ/Ϫ ) mice. The neointimal and medial areas were similar 1 to 3 weeks after electric injury of the femoral artery in ␣ 2 -AP ϩ/ϩ and ␣ 2 -AP Ϫ/Ϫ mice, resulting in comparable intima/media ratios (eg, 0.43Ϯ0.12 and 0.42Ϯ0.11 2 weeks after injury). Nuclear cell counts in cross-sectional areas of the intima of the injured region were also comparable in arteries from ␣ 2 -AP ϩ/ϩ and ␣ 2 -AP Ϫ/Ϫ mice (78Ϯ19 and 69Ϯ8). Fibrin deposition was not significantly different in arteries of both genotypes 1 day after injury, and no mural thrombosis was detected 1 week after injury. Fibrinolytic activity in femoral arterial sections, as monitored by fibrin zymography, was higher in ␣ 2 -AP Ϫ/Ϫ mice 1 week after injury (PϽ0.001) but was comparable in both genotypes 2 and 3 weeks after injury. Staining for elastin did not reveal significant degradation of the internal elastica lamina in either genotype. Immunocytochemical analysis revealed a comparable distribution pattern of ␣-actin-positive smooth muscle cells in both genotypes. These findings indicate that the endogenous fibrinolytic system of ␣ 2 -AP ϩ/ϩ mice is capable of preventing fibrin deposition after vascular injury and suggest that ␣ 2 -AP does not play a major role in smooth muscle cell migration and neointima formation in vivo. (Arterioscler

Evaluation of the profibrinolytic properties of an anti-TAFI monoclonal antibody in a mouse thromboembolism model

“…Mouse thrombin-antithrombin (TAT) complexes in plasma were determined with a commercial ELISA kit (Enzygnost TAT, Siemens). Plasmin-␣ 2 -antiplasmin complexes (PAP) in plasma were measured by ELISA as described elsewhere 24 using polyclonal antibodies against mouse ␣ 2 -antiplasmin and mouse plasminogen raised in rabbits. Coagulation assays were performed on the BCS-XP coagulation analyzer (Siemens) using reagents from the manufacturer and adapted procedures for mouse coagulation testing.…”

Vascular Functions of the Plasminogen Activation System

“…7 Consistent with this hypothesis, hyperfibrinogenemic mice exhibit enhanced neointima formation after carotid artery ligation compared with wild-type mice, 50 and depletion of plasma fibrinogen by administration of ancrod reduces intimal hyperplasia in mice after carotid artery ligation. 51 However, ␣ 2 -antiplasmin deficiency, which promotes fibrinolysis in vivo, 32 has no effect on neointima formation in mice, 52 suggesting that stabilization of fibrin by PAI-1 and/or ␣ 2 -antiplasmin does not play an essential role in murine vascular remodeling. …”

Neointima formation and thrombosis after vascular injury in transgenic mice overexpressing plasminogen activator inhibitor‐1 (PAI‐1)

“…Conflicting data on the effect of PAI‐1 and VN on restenosis after vascular injury may depend on which phase of the wound‐healing response and what part of the vasculature are analyzed; a critical feature appears to be the presence or absence of thrombus/fibrin [15]. This raised the hypothesis that PAI‐1 may inhibit neointima formation in the absence of fibrin (mechanical and electric injury models with only transient thrombosis [7,16–18]), but enhance it in the presence of fibrin (injury models induced with iron(III) chloride, rose Bengal or copper with persistent thrombus [8,9]).…”