Plasminogen Is a Critical Determinant of Vascular Remodeling in Mice

Abstract

Abstract-Extracellular proteolysis is likely to be a feature of vascular remodeling associated with atherosclerotic and restenotic arteries. To investigate the role of plasminogen-mediated proteolysis in remodeling, polyethylene cuffs were placed around the femoral arteries of mice with single and combined deficiencies in plasminogen and fibrinogen. Neointimal development occurred in all mice and was unaffected by genotype. Significant compensatory medial remodeling occurred in the cuffed arteries of control mice but not in plasminogen-deficient mice. Furthermore, focal areas of medial atrophy were frequently observed in plasminogen-deficient mice but not in control animals. A simultaneous deficit of fibrinogen restored the potential of the arteries of plasminogen-deficient mice to enlarge in association with neointimal development but did not eliminate the focal medial atrophy. An intense inflammatory infiltrate occurred in the adventitia of cuffed arteries, which was associated with enhanced matrix deposition. Adventitial collagen deposition was apparent after 28 days in control and fibrinogen-deficient arteries but not in plasminogendeficient arteries, which contained persistent fibrin. These studies demonstrate that plasmin(ogen) contributes to favorable arterial remodeling and adventitial collagen deposition via a mechanism that is related to fibrinogen, presumably fibrinolysis. In addition, these studies reveal a fibrin-independent role of plasminogen in preventing medial atrophy in challenged vessels. A rterial procedures such as coronary angioplasty result in an early or "acute" gain in arterial lumen diameter. Late loss of lumen diameter erodes this acute gain and is the single factor limiting the long-term clinical success of percutaneous interventional procedures, necessitating target vessel revascularization in up to 40% of patients. This loss of lumen diameter, or restenosis, was once thought to be solely a function of the development of a proliferative, smooth muscle cell-rich neointima, and much attention has been focused on efforts to prevent or reduce neointima formation. However, an increasing number of reports indicate that vascular remodeling (ie, alteration of the dimensions of the arterial wall) may play a greater role in determining arterial luminal diameter than neointimal size. 1-4 Studies on rodents, rabbits, and primates suggest that desirable postangioplasty lumen sizes occur when arterial diameter increases (favorable remodeling), whereas a decreased arterial diameter is associated with decreased lumen size (unfavorable remodeling), independent of neointimal size. 5-8 Increased hemodynamic pressure during either development or atherosclerotic neointima formation may promote favorable remodeling to maintain the relationship between blood flow and lumen size (compensatory remodeling). 9 Glagov et al 2 demonstrated that human coronary arteries enlarge in response to plaque formation until plaque area occupies Ϸ40% of the luminal area. These findings were later confirmed by angiographic ...

The Plasminogen Activation System Reduces Fibrosis in the Lung by a Hepatocyte Growth Factor-Dependent Mechanism

“…36 In a liver injury model, these mice have a marked impairment in the reparative removal of necrotic liver tissue and this impediment persisted in the absence of fibrin deposition. 56 Deficiency of plasminogen was also reported to impair wound healing in the skin, 57 large arteries, 58 and heart, 59 suggesting a significant involvement of plasmin in tissue repair. Considering that plasminogen activation is retarded during lung injury due to overexpression of PAI-1, restoration of plasmin action by urokinase treatment may provide a favorable environment for tissue repair in the lung, and consequently prevent the development of pulmonary fibrosis.…”

Increased Plasmin and Serine Proteinase Activity During Flow-Induced Intimal Atrophy in Baboon PTFE Grafts

“…Consistent with this idea is the observation that plasmin is required for the positive arterial remodeling observed after arterial injury. 15,35 In addition, arterial lesion development mediated by hyperlipidemia is accelerated by the absence of plasminogen, 36 indicating a protective role in atherogenesis. However, in the normolipemic context, plasmin is required for the intimal hyperplasia observed after arterial injury 37 and it has been demonstrated to play a role in aneurysmal expansion.…”

Vascular Functions of the Plasminogen Activation System

“…The development of intimal hyperplasia after vascular injury is diminished in plasminogen-deficient mice, supporting the concept that plasmin associated with vascular smooth muscle cells (VSMCs) enhances cell migration by fostering extracellular matrix degradation, either directly or indirectly by activating matrix metalloproteinases. 39,40 VSMCs express u-PA and its receptor ( Figure 2). Urokinase (u-PA) deficiency and pharmacological inhibition of u-PA receptor, but not t-PA deficiency, inhibit neointima formation in mice, suggesting that u-PAtriggered plasmin formation drives VSMC migration.…”